U.S. patent application number 10/115407 was filed with the patent office on 2002-11-14 for novel methods and compositions involving trk tyrosine kinase inhibitors and antineoplastic agents.
This patent application is currently assigned to Cephalon, Inc.. Invention is credited to Jones-Bolin, Susan E., Ruggeri, Bruce A..
Application Number | 20020169154 10/115407 |
Document ID | / |
Family ID | 26813168 |
Filed Date | 2002-11-14 |
United States Patent
Application |
20020169154 |
Kind Code |
A1 |
Ruggeri, Bruce A. ; et
al. |
November 14, 2002 |
Novel methods and compositions involving trk tyrosine kinase
inhibitors and antineoplastic agents
Abstract
Novel methods and compositions comprising antineoplastic agents
and trk tyrosine kinase inhibitors are disclosed. In preferred
embodiments, the antineoplastic agents comprise nucleoside analogs,
and the trk tyrosine kinase inhibitors comprise indolocarbazoles
and indenocarbazoles. The methods and compositions may be suitable
for the treatment of cancer, particularly pancreatic cancer.
Inventors: |
Ruggeri, Bruce A.; (West
Chester, PA) ; Jones-Bolin, Susan E.; (Thorndale,
PA) |
Correspondence
Address: |
Robert T. Hrubiec
CEPHALON, INC.
145 Brandywine Parkway
West Chester
PA
19380
US
|
Assignee: |
Cephalon, Inc.
|
Family ID: |
26813168 |
Appl. No.: |
10/115407 |
Filed: |
April 3, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60281366 |
Apr 4, 2001 |
|
|
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Current U.S.
Class: |
514/211.08 |
Current CPC
Class: |
A61K 31/553 20130101;
A61K 31/497 20130101; A61K 45/06 20130101; A61K 31/7068 20130101;
A61K 31/553 20130101; A61K 31/4965 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 31/52 20130101; A61P 35/00
20180101; A61K 31/4965 20130101; A61K 31/497 20130101; A61K 31/52
20130101; A61K 31/7068 20130101 |
Class at
Publication: |
514/211.08 |
International
Class: |
A61K 031/553 |
Claims
What is claimed is:
1. A method of treating cancer comprising administering to a
patient an effective amount of a trk tyrosine kinase inhibitor in
combination with an effective amount of an antineoplastic
agent.
2. The method of claim 1 wherein the trk tyrosine kinase inhibitor
is a compound of the following formula (I): 26(a) when Z.sup.1 and
Z.sup.2 are both hydrogen: (1) R is selected from the group
consisting of OH, O-n-alkyl of 1-6 carbons, and O-acyl of 2-6
carbons; (2) X is selected from the group consisting of H;
CONHC.sub.6H.sub.5 with the proviso that both R.sup.1and R.sup.2
are not Br; CH.sub.2Y wherein Y is: OR.sup.7 wherein R.sup.7is H or
acyl of 2-5 carbons; SOR.sup.8 wherein R.sup.5 is alkyl of 1-3
carbons, aryl, or a heterocyclic group including a nitrogen atom;
NR.sup.9R.sup.10 wherein R.sup.9 and R.sup.10 are each
independently H, alkyl of 1-3 carbons, Pro, Ser, Gly, Lys, or acyl
of 2-5 carbons, with the proviso that only one of R.sup.9 and
R.sup.10 is Pro, Ser, Gly, Lys or acyl; SR.sup.16 wherein R.sup.16
is an aryl, alkyl of 1-3 carbons or a heterocyclic group that
includes a nitrogen atom; N.sub.3; CO.sub.2CH.sub.3; S-Glc;
CONR.sup.11R.sup.12 wherein R.sup.11 and R.sup.12 are each
independently H, alkyl of 1-6 carbons, C.sub.6H.sub.5, or
hydroxyalkyl of 1-6 carbons, or R.sup.11 and R.sup.12 are combined
to form --CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--; CO.sub.2CH.sub.3;
CH.dbd.NNHCONH.sub.2; CONHOH; CH.dbd.NOH;
27CH.dbd.NN(R.sup.17).sub.2 wherein R.sup.17 represents aryl;
CH.sub.2NHCONBR.sup.18 wherein R.sup.18 is lower alkyl or aryl; or
X and R are combined together to form --CH.sub.2NHCO.sub.2--,
--CH.sub.2OC(CH.sub.3).sub.2O--, .dbd.O, or
--CH.sub.2N(CH.sub.3)CO.sub.2- --; (3) each of R.sup.1, R.sup.2,
R.sup.5 and R.sup.6 is, independently, H or up to two of them are
F; Cl; Br; I; NO.sub.2; CN; OH; NHCONHR.sup.13 wherein R.sup.13 is
C6Hs or alkyl of 1-3 carbons with the proviso that only one of
R.sup.1, R.sup.2, R.sup.5 and R.sup.6 is NHCONHR.sup.13;
CH.sub.2OR.sup.13; alkyl of 1-3 carbons; CH.sub.2OCONHR.sup.14; or
NHCO.sub.2R.sup.14; in which R.sup.14 is lower alkyl;
CH(SC.sub.6H.sub.5).sub.2 or CH(--SCH.sub.2CH.sub.2S--); or R.sup.1
is CH.sub.2S(O)PR.sup.21 where p=O or 1, and R.sup.21 is aryl,
alkyl of 1-3 carbons, a heterocyclic group that includes a nitrogen
atom, 28or CH.sub.2CH.sub.2N(CH.sub.3).sub.2, and R.sup.2, R.sup.5,
and R.sup.6 are H; or R.sup.1 is CH.dbd.NNR.sup.2R.sup.23, wherein
R.sup.22 and R.sup.23 are each independently H, alkyl of 1-3
carbons, C(.dbd.NH)NH.sub.2, or a heterocyclic group that includes
a nitrogen atom, or R.sup.22 and R.sup.23 are combined together to
form --(CH.sub.2).sub.4--, --(CH.sub.2CH.sub.2OCH.sub.2CH.sub.2)--,
or --(CH.sub.2CH.sub.2N(CH.sub.3- )CH.sub.2CH.sub.2)--, with the
proviso that R.sup.22 and R.sup.23 cannot both be H, and at least
one of R.sup.22 or R.sup.23 is H, except when both are alkyl, and
R.sup.2, R.sup.5 and R.sup.6 are H; and (b) when Z.sup.1 and
Z.sup.2 are both combined together to represent O; X is
CO.sub.2CH.sub.3; R is OH and R.sup.1, R.sup.2, R.sup.5 and R.sup.6
are each hydrogen.
3. The method of claim 2 wherein the compound of formula (I) has
the following formula (I-a): 29
4. The method of claim 3 wherein: R.sup.1 and R.sup.2 are selected
from H, alkyl, Cl, Br, CH.sub.2OH, CH.sub.2SOCH.sub.2CH.sub.3,
NHCONHC.sub.6H.sub.5, CH.sub.2SCH.sub.2CH.sub.3,
CH.sub.2SC.sub.6H.sub.5, NHCO.sub.2CH.sub.3,
CH.sub.2OC(.dbd.O)NHCH.sub.2CH.sub.3, CH.dbd.NNH, and
CH.sub.2OCH.sub.2CH.sub.3; R is selected from OH and OCH.sub.3; and
X is selected from OH, CH.sub.2OH, and CO.sub.2alkyl.
5. The method of claim 4 wherein the compound of formula (I-a) is
selected from: 30
6. The method of claim 5 wherein the compound of formula (a-a) is:
31
7. The method of claim 1 wherein the antineoplastic agent is
selected from the group consisting of fluoropyrimidines, pyrimidine
nucleosides and purines.
8. The method of claim 7 wherein the antineoplastic agent is a
fluoropyrimidine.
9. The method of claim 8 wherein the fluoropyrimidine is selected
from 5-fluorouracil and ftorafur.
10. The method of claim 7 wherein the antineoplastic agent is a
pyrimidine nucleoside.
11. The method of claim 10 wherein the pyrimidine nucleoside is
selected from the group consisting of gemcitabine, 5-azacytidine,
and cytosine arabinoside.
12. The method of claim 11 wherein the pyrimidine nucleoside is
gemcitabine.
13. The method of claim 7 wherein the antineoplastic agent is a
purine.
14. The method of claim 13 wherein the purine is 6-thioguanine.
15. The method of claim 1 wherein the antineoplastic agent is a
compound of the following formula (II): 32or a pharmaceutically
acceptable salt form thereof, wherein: R.sup.24 selected from H and
--C(.dbd.O)--R.sup.28; R.sup.25 is a base defined by one of the
following formulae: 33X' is selected from N and C--R.sup.27;
R.sup.26 is selected from H, alkyl and --C(.dbd.O)--R.sup.28;
R.sup.27 is selected from H, alkyl, amino, bromo, fluoro, chloro
and iodo; and R.sup.28 is selected from H and alkyl; and a
pharmaceutically acceptable carrier.
16. The method of claim 15 wherein R.sup.25 is a base of the
following formula 34
17. The method of claim 16 wherein X' is C--R.sup.27.
18. The method of claim 17 wherein R.sup.24, R.sup.26, R.sup.27 and
R.sup.28 are H.
19. The method of claim 1 wherein the trk tyrosine kinase inhibitor
is a compound of the following formula 35and the antineoplastic
agent is a compound of the following formula 36
20. The method of claim 19 wherein the cancer comprises pancreatic
cancer.
21. The method of claim 20 wherein the pancreatic cancer is
pancreatic ductal adenocarcinoma.
22. The method of claim 20 wherein the compound of formula (II-a)
is administered to the patient in a substantial excess relative to
the compound of formula (I-a-ii).
23. The method of claim 22 wherein the compound of formula (II-a)
and the compound of formula (I-a-ii) are administered to the
patient in a weight ratio of from about 4:1 to about 20:1.
24. The method of claim 1 wherein the cancer is selected from the
group consisting of carcinomas of the pancreas, prostate, breast,
thyroid, colon, and lung; malignant melanomas; glioblastomas;
neuroectodermal-derived tumors; and leukemias.
25. The method of claim 1 wherein the cancer is pancreatic
cancer.
26. The method of claim 25 wherein the pancreatic cancer is
pancreatic ductal adenocarcinoma.
27. A pharmaceutical composition comprising an effective amount of
a trk tyrosine kinase inhibitor and an effective amount of an
antineoplastic agent, together with a pharmaceutically acceptable
carrier.
28. The composition of claim 27 wherein the trk tyrosine kinase
inhibitor is a compound of the following formula (I): 37or a
stereoisomer or pharmaceutically acceptable salt form thereof,
wherein: (a) when Z.sup.1 and Z.sup.2 are both hydrogen: (1) R is
selected from the group consisting of OH, O-n-alkyl of 1-6 carbons,
and O-acyl of 2-6 carbons; (2) X is selected from the group
consisting of H; CONHC.sub.6H.sub.5 with the proviso that both
R.sup.1and R.sup.2 are not Br; CH.sub.2Y wherein Y is: OR.sup.7
wherein R.sup.7 is H or acyl of 2-5 carbons; SOR.sup.8wherein
R.sup.8 is alkyl of 1-3 carbons, aryl, or a heterocyclic group
including a nitrogen atom; NR.sup.9R.sup.10 wherein R.sup.9 and
R.sup.1 are each independently H, alkyl of 1-3 carbons, Pro, Ser,
Gly, Lys, or acyl of 2-carbons, with the proviso that only one of
R.sup.9 and R.sup.10 is Pro, Ser, Gly, Lys or acyl; SR.sup.16
wherein R.sup.1 is an aryl, alkyl of 1-3 carbons or a heterocyclic
group that includes a nitrogen atom; N.sub.3; CO.sub.2CH.sub.3;
S-Glc; CONR.sup.11R.sup.12 wherein R.sup.11 and R.sup.12 are each
independently H, alkyl of 1-6 carbons, C.sub.6H.sub.5, or
hydroxyalkyl of 1-6 carbons, or R.sup.11 and R.sup.12 are combined
to form --CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--; CO.sub.2CH.sub.3;
CH.dbd.NNHCONH.sub.2; CONHOH; CH.dbd.NOH;
CH.dbd.NNHC(.dbd.NH)NH.sub.2; 38CH.dbd.NN(R.sup.17).sub.2 wherein
R.sup.17 represents aryl; CH.sub.2NHCONHR.sup.18 wherein R.sup.18
is lower alkyl or aryl; or X and R are combined together to form
--CH.sub.2NHCO.sub.2--, --CH.sub.2OC(CH.sub.3).sub.2O--, =0, or
--CH.sub.2N(CH.sub.3)CO.sub.2--; (3) each of R.sup.1, R.sup.2,
R.sup.5 and R.sup.6 is, independently, H or up to two of them are
F; Cl; Br; I; NO.sub.2; CN; OH; NHCONHR wherein R is C.sub.6H.sub.5
or alkyl of 1-3 carbons with the proviso that only one of R.sup.1,
R.sup.2, R.sup.5 and R.sup.6 is NHCONHR.sup.13; CH.sub.2OR.sup.3;
alkyl of 1-3 carbons; CH.sub.2OCONHR.sup.14; or NHCO.sub.2R.sup.14;
in which R.sup.14 is lower alkyl; CH(SC.sub.6H.sub.5).sub.2 or
CH(--SCH.sub.2CH.sub.2S--); or R.sup.1 is
CH.sub.2S(O).sub.pR.sup.21 where p=O or 1, and R.sup.21 is aryl,
alkyl of 1-3 carbons, a heterocyclic group that includes a nitrogen
atom, 39or CH.sub.2CH.sub.2N(CH.sub.3).sub.2, and R.sup.2, R.sup.5,
and R.sup.6 are H; or R.sup.1 is CH.dbd.NNR.sup.22R.sup.23, wherein
R.sup.22 and R.sup.23 are each independently H, alkyl of 1-3
carbons, C(.dbd.NH)NH.sub.2, or a heterocyclic group that includes
a nitrogen atom, or R 22 and R.sup.23 are combined together to form
--(CH.sub.2).sub.4--, --(CH.sub.2CH.sub.2OCH.sub.2CH.sub.2)--, or
--(CH.sub.2CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2)--, with the proviso
that R.sup.22 and R.sup.23 cannot both be H, and at least one of
R.sup.22 or R.sup.23 is H, except when both are alkyl, and R.sup.2,
R.sup.5 and R.sup.6 are H; and (b) when Z.sup.1 and Z.sup.2 are
both combined together to represent O; X is CO.sub.2CH.sub.3; R is
OH and R.sup.1, R.sup.2, R.sup.5 and R.sup.6 are each hydrogen.
29. The composition of claim 28 wherein the compound of formula (I)
has the following formula (I-a): 40
30. The composition of claim 29 wherein: R.sup.1 and R.sup.2 are
selected from H, alkyl, Cl, Br, CH.sub.2OH,
CH.sub.2SOCH.sub.2CH.sub.3, NHCONHC.sub.6H.sub.5,
CH.sub.2SCH.sub.2CH.sub.3, CH.sub.2SC.sub.6H.sub.5,
NHCO.sub.2CH.sub.3, CH.sub.2OC(.dbd.O)NHCH.sub.2CH.sub.3,
CH.dbd.NNH, and CH.sub.2OCH.sub.2CH.sub.3; R is selected from OH
and OCH.sub.3; and X is selected from OH, CH.sub.2OH, and
CO.sub.2alkyl.
31. The composition of claim 30 wherein the compound of formula
(I-a) is selected from: 41
32. The composition of claim 31 wherein the compound of formula
(I-a) is: 42
33. The composition of claim 27 wherein the antineoplastic agent is
selected from the group consisting of fluoropyrimidines, pyrimidine
nucleosides and purines.
34. The composition of claim 33 wherein the antineoplastic agent is
a fluoropyrimidine.
35. The composition of claim 34 wherein the fluoropyrimidine is
selected from the group consisting of 5-fluorouracil and
ftorafur.
36. The composition of claim 33 wherein the antineoplastic agent is
a pyrimidine nucleoside.
37. The composition of claim 36 wherein the pyrimidine nucleoside
is selected from the group consisting of gemcitabine,
5-azacytidine, and cytosine arabinoside.
38. The composition of claim 37 wherein the pyrimidine nucleoside
is gemcitabine.
39. The composition of claim 33 wherein the antineoplastic agent is
a purine.
40. The composition of claim 39 wherein the purine is
6-thioguanine.
41. The composition of claim 27 wherein the antineoplastic agent is
a compound of the following formula (IL): 43or a pharmaceutically
acceptable salt form thereof, wherein: R.sup.24 is selected from H
and --C(.dbd.O)--R.sup.21; R.sup.25 is a base defined by one of the
following formulae: 44X' is selected from N and C--R.sup.27;
R.sup.26 is selected from H, alkyl and --C(.dbd.O)--R R.sup.27 is
selected from H, alkyl, amino, bromo, fluoro, chloro and iodo; and
R.sup.28 is selected from H and alkyl; and a pharmaceutically
acceptable carrier.
42. The composition of claim 41 wherein R.sup.25 is a base of the
following formula 45
43. The composition of claim 42 wherein X' is C--R.sup.27.
44. The composition of claim 43 wherein R.sup.24, R.sup.26,
R.sup.27 and R.sup.28 are H.
45. The composition of claim 27 wherein the trk tyrosine kinase
inhibitor is a compound of the following formula: 46and the
antineoplastic agent is a compound of the following formula: 47
46. The composition of claim 45 wherein the compound of formula
(II-a) is present in the composition in a substantial excess
relative to the compound of formula (I-a-ii).
47. The composition of claim 46 wherein the compound of formula
(II-a) and the compound of formula (I-a-ii) are present in the
composition in a weight ratio of from about 4:1 to about 20:1.
48. The composition of claim 27 which is in a single dosage unit
form.
49. A pharmaceutical kit comprising one or more containers
containing pharmaceutical dosage units comprising an effective
amount of a trk tyrosine kinase inhibitor in combination with an
effective amount of an antineoplastic agent.
50. The kit of claim 49 further comprising conventional
pharmaceutical kit components.
51. The method of claim 1 wherein the trk tyrosine kinase inhibitor
is a compound of the following formula (III): 48or a stereoisomer
or pharmaceutically acceptable salt form thereof, wherein: R.sup.1
is selected from the group consisting of: a) H, substituted or
unsubstituted C.sub.1-4 alkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
heteroarylalkyl; b) --C(.dbd.O)R.sup.9, where R.sup.9 is selected
from the group consisting of H, C.sub.1-4 alkyl, aryl and
heteroaryl; c) --OR.sup.10, where R.sup.10 is selected from the
group consisting of H and C.sub.1-4 alkyl; d) --C(.dbd.O)NH.sub.2,
--NR.sup.11R.sup.12-(CH.sub.2).sub.pNR.sup.11R.sup.1- 2,
--(CH.sub.2).sub.pOR.sup.10, --O(CH.sub.2).sub.pOR.sup.10 and
--O(CH.sub.2).sub.pNR.sup.11R.sup.12, wherein p is from 1 to 4; and
wherein either 1) R.sup.11 and R.sup.12 are each independently
selected from the group consisting of H and C.sub.1-4 alkyl; or 2)
R.sup.11 and R.sup.12 together form a linking group of the formula
--(CH.sub.2).sub.2--X.sup.1--(CH.sub.2).sub.2--, wherein X.sup.1 is
selected from the group consisting of --O--, --S--, and
--CH.sub.2--; R.sup.2 is selected from the group consisting of H,
C.sub.1-4 alkyl, --OH, and C.sub.1-4 alkoxy; R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are each independently selected from the group
consisting of: a) H, aryl, heteroaryl, F, Cl, Br, I, --CN,
CF.sub.3, --NO.sub.2, --OH, --OR.sup.9,
--O(CH.sub.2).sub.pNR.sup.11R.sup.12, --OC(.dbd.O)R.sup.9,
--OC(.dbd.O)NR.sup.2R.sup.7, --OC(.dbd.O)NR.sup.11R.sup.12,
--O(CH.sub.2).sub.pOR.sup.11, --CH.sub.2OR.sup.10,
NR.sup.11R.sup.12, --NR.sup.10S(.dbd.O).sub.2R.sup.9,
NR.sup.10C(.dbd.O)R.sup.9; b) --CH.sub.2OR.sup.14, wherein R.sup.14
is the residue of an amino acid after the hydroxyl group of the
carboxyl group is removed; c)
--NR.sup.10C(.dbd.O)NR.sup.11R.sup.12, --CO.sub.2R.sup.2,
--C(.dbd.O)R.sup.2, --C(.dbd.O)NR.sup.11R.sup.12,
--CH.dbd.NOR.sup.2, --CH.dbd.NR.sup.9,
--(CH.sub.2).sub.pNR.sup.11R.sup.12, --(CH.sub.2).sub.pNHR.sup.14,
or --CH.dbd.NNR.sup.2R.sup.2A wherein R.sup.2A is the same as
R.sup.2; d) --S(O).sub.yR.sup.2--(CH.sub.2).sub.p-
S(O).sub.yR.sup.9, --CH.sub.2S(O).sub.yR.sup.14 wherein y is 0, 1
or 2; e) C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
wherein each alkyl, alkenyl, or alkynyl group may substituted with
1 to 3 groups selected from the group consisting of: C.sub.6-10
arylalkyl, heteroaryl, arylalkoxy, heterocycloalkoxy,
hydroxyalkoxy, alkyloxy-alkoxy, hydroxyalkylthio, alkoxyalkylthio,
F, Cl, Br, I, --CN, --NO.sub.2, --OH, --OR.sup.9,
--X.sup.2(CH.sub.2).sub.pNR.sup.11R.sup.12,
--X.sup.2(CH.sub.2).sub.pC(.dbd.O)NR.sup.11R.sup.12,
--X.sup.2(CH.sub.2).sub.pOC(.dbd.O)NR.sup.11R.sup.12,
--X.sup.2(CH.sub.2).sub.pCO.sub.2R.sup.9, --X.sup.2
(CH.sub.2).sub.pS(O).sup.yR.sup.9,
--X.sup.2(CH.sub.2).sub.pNR.sup.10C(.d- bd.O)NR.sup.11R.sup.12,
--OC(.dbd.O)R.sup.9, --OCONHR.sup.2, --O-tetrahydropyranyl,
--NR.sup.11R.sup.12, --NR.sup.10C(.dbd.O)R.sup.9,
--NR.sup.10CO.sub.2R.sup.9, --NR.sup.10C(.dbd.O)NR.sup.11R.sup.12,
--NHC(.dbd.NH)NH.sub.2, NR.sup.10S(O).sub.2R.sup.9,
--S(O).sub.yR.sup.9, --CO.sub.2R.sup.2,
--C(.dbd.O)NR.sup.11R.sup.2, --C(.dbd.O)R.sup.2,
--CH.sub.2OR.sup.10, --CH.dbd.NNR.sup.2R.sup.2A,
--CH.dbd.NOR.sup.2, --CH.dbd.NR.sup.9,
--CH.dbd.NNHCH(N.dbd.NH)NH.sub.2,
--S(.dbd.O).sub.2NR.sup.2R.sup.2A, --P(.dbd.O)(OR.sup.10).sub.2,
--OR.sup.14, and a monosaccharide having from 5 to 7 carbons
wherein each hydroxyl group of the monosaccharide is independently
either unsubstituted or is replaced by H, C.sub.1-4 alkyl,
alkylcarbonyloxy having from 2 to 5 carbons, or C.sub.1-4 alkoxy;
wherein X.sup.2 is O, S, or NR.sup.10; R.sup.7 and R.sup.8 are each
independently selected from the group consisting of H, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, substituted or unsubstituted C.sub.6-10
arylalkyl, substituted or unsubstituted heteroarylalkyl,
--(CH.sub.2).sub.pOR.sup.10, --(CH.sub.2).sub.pOC(.dbd.O-
)NR.sup.11R.sup.12, and --(CH.sub.2).sub.pNR.sup.11R.sup.12; or
R.sup.7 and R.sup.8 together form a linking group of the formula
--CH.sub.2--X.sup.3--CH.sub.2--; wherein X.sup.3 is X.sup.2 or a
bond; m and n are each independently 0, 1, or 2; Y is selected from
the group consisting of --O--, --S--, --N(R.sup.10)--,
--N+(O--)(R.sup.10)--, --N(OR.sup.10)--, and --CH.sub.2--; Z is
selected from the group consisting of a bond, --O--, --CH.dbd.CH--,
--S--, --C(.dbd.O)--, --CH(ORO)--, --N(RO)--, --N(OR.sup.10)--,
CH(NR.sup.11R.sup.12)--, --C(.dbd.O)N(R.sup.17),
N(R.sup.17)C(.dbd.O)--, --N(S(O).sub.yR.sup.9)--,
--N(S(O).sub.yNR.sup.11R.sup.12)--, --N(C(.dbd.O)R.sup.17)--,
--C(R.sup.5 R.sup.16)--, --N.sup.+(O.sup.-)(R.sup.10)--,
--CH(OH)--CH(OH)--, and --CH(O(C.dbd.O)R )CH(OC(.dbd.O)R.sup.9A)--;
wherein R.sup.9A is the same as R.sup.9; R.sup.15 and R.sup.16 are
independently selected from the group consisting of H, --OH,
--C(.dbd.O)R.sup.10, --O(C.dbd.O)R.sup.9, hydroxyalkyl, and
--CO.sub.2R.sup.10; R.sup.17 is selected from the group consisting
of H, C.sub.1-6 alkyl, aryl, and heteroaryl; A.sup.1 and A.sup.2
are selected from the group consisting of H, H; H, OR.sup.2; H,
--SR.sup.2; H, --N(R.sup.2).sub.2; and a group wherein A.sup.1 and
A.sup.2 together form a moiety selected from the group consisting
of .dbd.O, .dbd.S, and .dbd.NR.sup.2.
52. The method of claim 51 wherein the compound of formula (III)
has the following formula (III-a): 49wherein: R.sup.1 is H or
substituted or unsubstituted C.sub.1-4 alkyl; R.sup.7 and R.sup.8
are each independently H or substituted or unsubstituted C.sub.1-4
alkyl.
53. The method of claim 52 wherein: R.sup.1 is H; R.sup.3 and
R.sup.5 are each independently H, aryl, F, Cl, Br, I, --OR.sup.9,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, or C.sub.2-8 alkynyl.
54. The method of claim 53 wherein the compound of formula (III-a)
is: 50
55. The method of claim 1 wherein the trk tyrosine kinase inhibitor
is a compound of the following formula: 51and the antineoplastic
agent is a compound of the following formula: 52
56. The method of claim 55 wherein the cancer comprises pancreatic
cancer.
57. The method of claim 56 wherein the pancreatic cancer is
pancreatic ductal adenocarcinoma.
58. The method of claim 56 wherein the compound of formula (II-a)
is administered to the patient in a substantial excess relative to
the compound of formula (III-a-i).
59. The method of claim 58 wherein the compound of formula (II-a)
and the compound of formula (III-a-i) are administered to the
patient in a weight ratio of from about 4:1 to about 20:1.
60. The composition of claim 27 wherein the trk tyrosine kinase
inhibitor is a compound of the following formula (III): 53or a
stereoisomer or pharmaceutically acceptable salt form thereof,
wherein: R.sup.1 is selected from the group consisting of: a) H,
substituted or unsubstituted C.sub.1-4 alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl,
substituted or unsubstituted heteroaryl, or substituted or
unsubstituted heteroarylalkyl; b) --C(.dbd.O)R.sup.9, where R.sup.9
is selected from the group consisting of H, C.sub.1-4 alkyl, aryl
and heteroaryl; c) --OR.sup.10, where R.sup.10 is selected from the
group consisting of H and C.sub.1-4 alkyl; d) --C(.dbd.O)NH.sub.2,
--NR.sup.11R.sup.12, --(CH.sub.2).sub.pNR.sup.11R.su- p.12,
--(CH.sub.2).sub.pOR.sup.10, --O(CH.sub.2).sub.pOR.sup.10 and
--O(CH.sub.2).sub.pNR.sup.11R.sup.2, wherein p is from 1 to 4; and
wherein either 1) R.sup.11 and R.sup.12 are each independently
selected from the group consisting of H and C.sub.1-4 alkyl; or 2)
R.sup.11 and R.sup.12 together form a linking group of the formula
--(CH.sub.2).sub.2--X.sup.1--(CH.sub.2).sub.2--, wherein X.sup.1 is
selected from the group consisting of --O--, --S--, and
--CH.sub.2--; R.sup.2 is selected from the group consisting of H,
C.sub.1-4 alkyl, --OH, and C.sub.1-4 alkoxy; R.sup.3, R.sup.4,
R.sup.5 and R.sup.6 are each independently selected from the group
consisting of: a) H, aryl, heteroaryl, F, Cl, Br, I, --CN,
CF.sub.3, --NO.sub.2, --OH, --OR.sup.9,
--O(CH.sub.2).sub.pNR.sup.11R.sup.12, --OC(.dbd.O)R.sup.9,
--OC(.dbd.O)NR R.sup.7--OC(.dbd.O)NR.sup.11R.sup.12,
--O(CH.sub.2).sub.pOR.sup.10, --CH.sub.2OR.sup.10,
--NR.sup.11R.sup.12--NR.sup.10S(.dbd.O).sub.2R.sup.9- ,
--NR.sup.10C(.dbd.O)R.sup.9; b) --CH.sub.2OR 14, wherein R.sup.14
is the residue of an amino acid after the hydroxyl group of the
carboxyl group is removed; c)
--NR.sup.10C(.dbd.O)NR.sup.11R.sup.12, --CO.sub.2R.sup.2,
--C(.dbd.O)R.sup.2, --C(.dbd.O)NR.sup.11R.sup.12,
--CH.dbd.NOR.sup.2, --CH.dbd.NR.sup.9,
--(CH.sub.2).sub.pNR.sup.11R.sup.12, --(CH.sub.2).sub.pNHR.sup.4,
or CH.dbd.NNR.sup.2R.sup.2A wherein R.sup.2A is the same as R d)
_S(O)R.sup.2--(CH.sub.2).sub.pS(O),R.sup.9,
--CH.sub.2S(O).sub.yR.sup.14 wherein y is 0, 1 or 2; e) C.sub.1-8
alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, wherein each alkyl,
alkenyl, or alkynyl group may substituted with 1 to 3 groups
selected from the group consisting of: C.sub.6-10 arylalkyl,
heteroaryl, arylalkoxy, heterocycloalkoxy, hydroxyalkoxy,
alkyloxy-alkoxy, hydroxyalkylthio, alkoxyalkylthio, F, Cl, Br, I,
--CN, --NO.sub.2, --OH, --OR.sup.9,
--X.sup.2(CH.sub.2).sub.pNR.sup.11R.sup.12,
--X.sup.2(CH.sub.2).sub.pC(.d- bd.O)NR.sup.11R.sup.12,
--X.sup.2(CH.sub.2),OC(.dbd.O)NR.sup.1R.sup.12,
--X.sup.2(CH.sub.2).sub.pCO.sub.2R.sup.9,
--X.sup.2(CH.sub.2).sub.pS(O).s- ub.yR.sup.9,
--X.sup.2(CH.sub.2).sub.pNR.sup.10C(.dbd.O)NR.sup.11R.sup.12,
--OC(.dbd.O)R.sup.9, --OCONHR.sup.2, --O-tetrahydropyranyl,
--NR.sup.11R.sup.12, --NR.sup.10C(.dbd.O)R.sup.9,
--NR.sup.10CO.sub.2R.su- p.9,
--NR.sup.10C(.dbd.O)NR.sup.11R.sup.12, --NHC(.dbd.NH)NH.sub.2,
NR.sup.10S(O).sub.2R.sup.9, --S(O).sub.yR.sup.9--CO.sub.2R.sup.2,
--C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)R.sup.2,
--CH.sub.2OR.sup.10, --CH.dbd.NNR.sup.2R.sup.2A,
--CH.dbd.NOR.sup.2, --CH.dbd.NR.sup.9,
--CH.dbd.NNHCH(N.dbd.NH)NH.sub.2,
--S(.dbd.O).sub.2NR.sup.2R.sup.2A, --P(.dbd.O)(OR.sup.10).sub.2,
--OR.sup.14, and a monosaccharide having from 5 to 7 carbons
wherein each hydroxyl group of the monosaccharide is independently
either unsubstituted or is replaced by H, C.sub.1-4 alkyl,
alkylcarbonyloxy having from 2 to 5 carbons, or C.sub.1-4 alkoxy;
wherein X.sup.2 is O, S, or NR.sup.10; R.sup.7 and R.sup.8 are each
independently selected from the group consisting of H, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, substituted or unsubstituted C.sub.6-10
arylalkyl, substituted or unsubstituted heteroarylalkyl,
--(CH.sub.2).sub.pOR.sup.10,
--(CH.sub.2).sub.pOC(.dbd.O)NR.sup.11R.sup.12, and
--(CH.sub.2).sub.pNR.sup.11R.sup.12; or R.sup.7 and R.sup.8
together form a linking group of the formula
--CH.sub.2--X.sup.3--CH.sub.2--; wherein X.sup.3 is X.sup.2 or a
bond; m and n are each independently 0, 1, or 2; Y is selected from
the group consisting of --O--, --S--, --N(R.sup.10)--,
--N.sup.+(O.sup.-)(R.sup.10)--, --N(OR.sup.10)--, and --CH.sub.2--;
Z is selected from the group consisting of a bond, --O--,
--CH.dbd.CH--, --S--, --C(.dbd.O)--, --CH(OR.sup.10),
--N(R.sup.10)--, --N(OR.sup.10)--, CH(NR.sup.11R.sup.12)
--C(.dbd.O)N(R.sup.10) N(R.sup.7)C(.dbd.O)--,
--N(S(O).sub.yR.sup.9)--, --N(S(O).sub.yNR.sup.11R.sup.12)--,
--N(C(.dbd.O)R.sup.17)--, --C(R.sup.15R.sup.16),
--N.sup.+(O.sup.-)(R.sup- .10)--, --CH(OH)--CH(OH)--, and
--CH(O(C.dbd.O)R.sup.9)CH(OC(.dbd.O)R.sup.- 9A)--; wherein R.sup.9A
is the same as R.sup.9; R.sup.15 and R.sup.16 are independently
selected from the group consisting of H, --OH, --C(.dbd.O)R.sup.10,
--O(C.dbd.O)R.sup.9, hydroxyalkyl, and --CO.sub.2R.sup.10; R.sup.17
is selected from the group consisting of H, C.sub.1-6 alkyl, aryl,
and heteroaryl; A.sup.1 and A.sup.2 are selected from the group
consisting of H, H; H, OR.sup.2; H, --SR.sup.2; H,
--N(R.sup.2).sub.2; and a group wherein A.sup.1 and A.sup.2
together form a moiety selected from the group consisting of
.dbd.O, .dbd.S, and .dbd.NR.sup.2.
61. The composition of claim 60 wherein the compound of formula
(1R) has the following formula (III-a): 54wherein: R.sup.1 is H or
substituted or unsubstituted C.sub.1-4 alkyl; R.sup.7 and R.sup.8
are each independently H or substituted or unsubstituted C.sub.1-4
alkyl.
62. The composition of claim 61 wherein: R.sup.1 is H; R.sup.3 and
R.sup.5 are each independently H, aryl, F, Cl, Br, I, --OR.sup.9,
C.sub.1-8 alkyl, C.sub.2-8 alkenyl, or C.sub.2-8 alkynyl.
63. The composition of claim 62 wherein the compound of formula
(III-a) is: 55
64. The composition of claim 27 wherein the trk tyrosine kinase
inhibitor is a compound of the following formula 56and the
antineoplastic agent is a compound of the following formula 57
65. The composition of claim 64 wherein the compound of formula
(III-a) is present in the composition in a substantial excess
relative to the compound of formula (III-a-i).
66. The composition of claim 65 wherein the compound of formula
(III-a) and the compound of formula (III-a-i) are present in the
composition in a weight ratio of from about 4:1 to about 20:1.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel methods and
compositions involving trk tyrosine kinase inhibitors and
antineoplastic agents. More particularly, the present invention
relates to novel methods and compositions involving trk tyrosine
kinase inhibitors and antineoplastic agents for the treatment of
cancer, including pancreatic cancer.
BACKGROUND OF THE INVENTION
[0002] Broadly speaking, the main approaches to cancer treatment
include radiation therapy, surgery and chemotherapy. Many patients
undergoing these treatments, however, do not experience
substantial, sustained, favorable responses.
[0003] Radiation and surgical approaches generally necessitate a
complete or substantially complete removal or destruction of all
cancer cells in order to render effective treatment. In practice,
such results can rarely be achieved, and are extremely difficult
where metastasis has occurred. Moreover, radiation therapy and
surgery generally aid only in the local control of cancer and
typically offer limited benefit for patient survival.
[0004] Chemotherapeutic agents have been developed that exhibit
antitumor activity against a variety of solid tumors, but the
prognosis and overall survival rate of cancer patients undergoing
chemotherapy remains poor. Furthermore, the use of chemotherapeutic
agents is often associated with systemic toxicity, which may result
in severe side effects such as nausea, vomiting, mucositis,
neutropenia, thrombocytopenia, and anorexia.
[0005] Chemotherapeutic agents include nucleoside analogs and trk
tyrosine kinase inhibitors. Gemcitabine
(2',2'-difluorodeoxycytidine) is a nucleoside analog, the
incorporation of which into DNA has been shown to prevent the
elongation of nascent DNA strands. Gemcitabine has exhibited
antitumor activity against a variety of tumors. See Lund; B., et
al. J. Natl. Cancer Inst. 86:1530-1533, 1994; Hertel, L. W., et al.
Cancer Res.50:4417-4422, 1990; Grindley, G. B., et al. Cancer
Invest. 8:313-318, 1990. Treatment with gemcitabine, however, as
with other chemotherapeutic agents, has not been shown to
significantly enhance patient survival in most cases. See
Rothenberg, M. L. et al. Ann. Oncol. 7:347-353, 1996.
[0006] Neurotrophins regulate growth, differentiation and survival
of central and peripheral neurons. Neurotrophin growth factors bind
to and activate cell surface receptors, trks, which exhibit
tyrosine kinase activity. The binding of neurotrophin to a trk
receptor leads to receptor oligomerization and tyrosine
phosphorylation of specific intracellular substrates. A possible
role for neurotrophins in the invasive and metastatic phenotype of
specific tumor types, and the modulation of cell survival pathways
in other types of cancer, has recently been recognized. See
Ruggeri. B. A., et al. Current Med. Chem. 6:845-857, 1999.
Furthermore, trk tyrosine kinase inhibitors have been shown to
exhibit antitumor activity. See Miknyoczki, S. J., et al. Clin.
Cancer Res. 5:2205-2212, 1999. The antitumor efficacy of trk
tyrosine kinase inhibitors, however, is generally not significantly
greater than that of other chemotherapeutic agents. Id. A need thus
exists for improved cancer treatments that may desirably prolong
the survival of cancer patients, preferably without producing
severe side effects. The present invention is directed to these, as
well as other important ends.
SUMMARY OF THE INVENTION
[0007] The present invention is directed, in part, to novel methods
and compositions for treating cancer. Specifically, in one
embodiment, methods of treating cancer are provided that comprise
administering to a patient an effective amount of a trk tyrosine
kinase inhibitor in combination with an effective amount of an
antineoplastic agent.
[0008] Another embodiment of the invention relates to
pharmaceutical compositions comprising an effective amount of a trk
tyrosine kinase inhibitor and an effective amount of an
antineoplastic agent, together with a pharmaceutically acceptable
carrier.
[0009] Yet another embodiment of the invention relates to
pharmaceutical kits comprising one or more containers containing
pharmaceutical dosage units comprising an effective amount of a trk
tyrosine kinase inhibitor in combination with an effective amount
of an antineoplastic agent.
[0010] In preferred embodiments, the methods, compositions, and
kits of the present invention involve a trk tyrosine kinase
inhibitor of the following formula (I): 1
[0011] or a stereoisomer or pharmaceutically acceptable salt form
thereof, wherein:
[0012] (a) when Z.sup.1 and Z.sup.2 are both hydrogen:
[0013] (1) R is selected from the group consisting of OH, O-n-alkyl
of 1-6 carbons, and O-acyl of 2-6 carbons;
[0014] (2) X is selected from the group consisting of H;
CONHC.sub.6H.sub.5 with the proviso that both R.sup.1 and R.sup.2
are not Br; CH.sub.2Y wherein Y is:
[0015] OR.sup.7 wherein R.sup.7 is H or acyl of 2-5 carbons;
[0016] SOR.sup.8 wherein R8 is alkyl of 1-3 carbons, aryl, or a
heterocyclic
[0017] group including a nitrogen atom;
[0018] NR.sup.9R.sup.10 wherein R.sup.9 and R10 are each
independently H, alkyl of 1-3 carbons, Pro, Ser, Gly, Lys, or acyl
of 2-5 carbons, with the proviso that only one of R.sup.9 and
R.sup.10 is Pro, Ser, Gly, Lys or acyl;
[0019] SR.sup.16 wherein R.sup.16 is an aryl, alkyl of 1-3 carbons
or a heterocyclic group that includes a nitrogen atom;
[0020] N.sub.3; CO.sub.2CH.sub.3; S-Glc;
[0021] CONR.sup.11R.sup.12 wherein R.sup.11 and R.sup.12 are each
independently H, alkyl of 1-6 carbons, C.sub.6H.sub.5, or
hydroxyalkyl of 1-6 carbons, or R.sup.11 and R.sup.12 are combined
to form --CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--;
[0022] CO.sub.2CH.sub.3; CH.dbd.NNHCONH.sub.2; CONHOH; CH.dbd.NOH;
2
[0023] CH.dbd.NN(R.sup.17).sub.2 wherein R.sup.17 represents
aryl;
[0024] CH.sub.2NHCONHR.sup.18 wherein R.sup.18 is lower alkyl or
aryl; or
[0025] X and R are combined together to form
--CH.sub.2NHCO.sub.2--, --CH.sub.2OC(CH.sub.3).sub.2O--, .dbd.O, or
--CH.sub.2N(CH.sub.3)CO.sub.2- --;
[0026] (3) each of R.sup.1, R.sup.2, R.sup.5 and R.sup.6 is,
independently, H or up to two of them are F; Cl; Br; I; NO.sub.2;
CN; OH; NHCONHR.sup.13 wherein R.sup.13 is C.sub.6Hs or alkyl of
1-3 carbons with the proviso that only one of R.sup.1, R.sup.2,
R.sup.5 and R.sup.6 is NHCONHR.sup.13; CH.sub.2OR ; alkyl of 1-3
carbons;
[0027] CH.sub.2OCONHR.sup.14; or NHCO.sub.2R.sup.14; in which
R.sup.14 is lower alkyl; CH(SC.sub.6H.sub.5).sub.2 or
[0028] CH(--SCH.sub.2CH.sub.2S--); or R.sup.1 is
CH.sub.2S(O).sub.pR.sup.2- 1 where p=0 or 1, and R.sup.21 is aryl,
alkyl of 1-3 carbons, a heterocyclic group that includes a nitrogen
atom, 3
[0029] or CH.sub.2CH.sub.2N(CH.sub.3).sub.2, and R.sup.2, R5, and R
are H; or R.sup.1 is CH.dbd.NNR.sup.2R.sup.3, wherein R.sup.22 and
R.sup.23 are each independently H, alkyl of 1-3 carbons,
C(.dbd.NH)NH.sub.2, or a heterocyclic group that includes a
nitrogen atom, or R.sup.22 and R.sup.23 are combined together to
form --(CH.sub.2).sub.4--, --(CH.sub.2CH.sub.2OCH.sub.2CH.sub.2)--,
or --(CH.sub.2CH.sub.2N(CH.sub.3- )CH.sub.2CH.sub.2)--, with the
proviso that R.sup.22 and R.sup.23 cannot both be H, and at least
one of R.sup.22 or R.sup.23 is H, except when both are alkyl, and
R.sup.2, R.sup.5 and R.sup.6are H;
[0030] and
[0031] (b) when Z.sup.1 and Z.sup.2 are both combined together to
represent 0; X is CO.sub.2CH.sub.3; R is OH and R.sup.1, R.sup.2,
R.sup.5 and R.sup.6 are each hydrogen.
[0032] In additional preferred embodiments, the present methods,
compositions and kits involve an antineoplastic agent of the
following formula (II): 4
[0033] or a pharmaceutically acceptable salt form thereof,
wherein:
[0034] R.sup.24 is selected from H and --C(.dbd.O)--R28;
[0035] R.sup.25 is a base defined by one of the following formulae:
5
[0036] X' is selected from N and C--R.sup.27;
[0037] R.sup.26 is selected from H. alkyl and
--C(.dbd.O)--R.sup.28;
[0038] R.sup.27 is selected from H, alkyl, amino, bromo, fluoro,
chloro and iodo; and
[0039] R.sup.28 is selected from H and alkyl;
[0040] and a pharmaceutically acceptable carrier.
[0041] In other preferred embodiments, the present invention
involves a trk kinase inhibitor of the following formula (III):
6
[0042] or a stereoisomer or pharmaceutically acceptable salt form
thereof, wherein A.sup.1, A.sup.2, R.sup.1--R.sup.8, Y, Z, m and n
are as defined below.
[0043] These and other aspects of the invention will become more
apparent from the following detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0044] FIG. 1 illustrates Kaplan-Meier survival curves for nude
mice orthotopically implanted with human pancreatic ductal
adenocarcinoma (PDAC) xenografts and administered the compound of
formula (I-a-i) and gemcitabine alone or in combination. The data
indicate differences in survival (the number of days dosed) for
untreated mice (U), vehicle treated mice (V), mice who received the
compound of formula (I-aii) only (A), mice who received gemcitabine
only (H), and mice who received a combination of the compound of
formula (I-ai) and gemSitabine (D).
[0045] FIG. 2 illustrates Kaplan-Meier survival curves for nude
mice orthotopically implanted with human pancreatic ductal
adenocarcinoma (PDAC) xenografts and administered the compound of
formula (m-a-i) and gemcitabine alone or in combination. The data
indicate differences in survival (the number of days dosed) for
untreated mice (U), vehicle treated mice (V), mice who received the
compound of formula (I-a-i) only (A), mice who received gemcitabine
only (H), and mice who received a combination of the compound of
formula (I-a-ii) and gemcitabine (D).
DETAILED DESCRIPTION OF THE INVENTION
[0046] As employed above and throughout the disclosure, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings.
[0047] The core structures provided herein are presented by way of
general guidance, and are not to be taken as limiting the scope of
the invention. For example, certain cores indicate the presence of
certain atoms for illustrative purposes. It will be appreciated
that such atoms may bonded to additional groups, or may be further
substituted without deviating from the spirit of the invention.
[0048] As used herein, "indolocarbazole" is intended to indicate a
compound of the following formula: 7
[0049] wherein at least one of G, X, or W is nitrogen and B and F
are aryl or heteroaryl groups.
[0050] These compounds are intended to include, but are not limited
to, structures in which the nitrogens of the carbazole and the
indole form a cyclic bridged moiety: 8
[0051] The indolocarbazoles and indenocarbazoles suitable for use
in the methods and compositions of the present invention are stable
compounds. As used herein "stable compound" or "stable structure"
is meant to indicate a compound that is sufficiently robust to
survive isolation to a useful degree of purity from a reaction
mixture, and preferably capable of formulation into an efficacious
therapeutic agent.
[0052] The indolocarbazoles and indenocarbazoles may be further
substituted. As used herein, "substituted" is intended to indicate
that one or more hydrogen atoms on the indicated atom is replaced
with a selected group referred to herein as a "substituent",
provided that the substituted atom's valency is not exceeded, and
that the substitution results in a stable compound.
[0053] As used herein, the term "alkyl" means a straight-chain,
cyclic, or branched alkyl group having 1 to 8 carbon atoms, such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isoamyl, neopentyl, 1-ethylpropyl, hexyl,
octyl, cyclopropyl, and cyclopentyl. The alkyl moiety of
alkyl-containing groups, such as alkoxy, alkoxycarbonyl, and
alkylaminocarbonyl groups, has the same meaning as alkyl defined
above. Lower alkyl groups, which are preferred, are alkyl groups as
defined above which contain 1 to 4 carbons.
[0054] Alkyl groups and alkyl moieties contained within substituent
groups such as aralkyl, alkoxy, arylalkoxy, hydroxyalkoxy,
alkoxy-alkoxy, hydroxy-alkylthio, alkoxy-alkylthio,
alkylcarbonyloxy, hydroxyalkyl and acyloxy groups may be
substituted or unsubstituted. A substituted alkyl group has 1 to 3
independently-selected substituents, preferably hydroxy, lower
alkoxy, lower alkoxy-alkoxy, halogen, carboxyl, lower
alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino,
dioxolane, dioxane, dithiolane, dithione, furan, lactone, or
lactam.
[0055] As used herein, the "acyl" moiety of acyl-containing groups
such as acyloxy groups is intended to include a straight-chain,
branched, or cyclic alkanoyl group having 1 to 6 carbon atoms, such
as formyl, acetyl, propanoyl, butyryl, valeryl, pivaloyl or
hexanoyl.
[0056] As used herein, the term "carbocyclic" refers to cyclic
groups in which the ring portion is composed solely of carbon
atoms. These include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexl, cycloheptyl, cyclooctyl. The
term "carbocyclic aromatic ring" is intended to include carbocyclic
rings which are also aryl rings. The terms "heterocyclo" and
"heterocyclic" refer to cyclic groups in which the ring portion
includes at least one heteroatom such as O, N, or S. Heterocyclyl
groups include heteroaryl and heteroalkyl groups.
[0057] As used herein the term "aryl" means an aromatic ring having
6 to 12 carbon atoms such as phenyl, biphenyl and naphthyl, with
aromatic rings of 6 to 10 carbons being preferred. Preferred aryl
groups include unsubstituted or substituted phenyl and naphthyl
groups. The term "heteroaryl" as used herein denotes an aryl group
in which one or more ring carbon atoms is replaced by a hetero
(i.e., non-carbon) atom such as O, N or S. Preferred heteroaryl
groups include pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl,
imidazolyl, triazolyl, tetrazolyl, quinolyl, isoquinolyl,
benzoimidazolyl, thiazolyl, pyrazolyl, and benzothiazolyl groups.
The term "heterocycloalkyl" denotes a cycloalkyl group in which , O
one or more ring carbon atoms is replaced by hetero atoms such as
O, N, or S.
[0058] As used herein, the term "aralkyl" (or "arylalkyl") is
intended to denote a group having from 7 to 15 carbons, consisting
of an alkyl group that bears an aryl group. Examples of aralkyl
groups include, but are not limited to, benzyl, phenethyl,
benzhydryl and naphthylmethyl groups. Substituted aryl, substituted
heterocyclic and substituted aralkyl groups each have 1 to 3
independently selected substituents that are preferably lower
alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro,
amino, mono- or di-lower alkylamino, and halogen.
[0059] Preferred heterocyclic groups formed with a nitrogen atom
include pyrrolidinyl, piperidinyl, piperidino, morpholinyl,
morpholino, thiomorpholino, N-methylpiperazinyl, indolyl,
isoindolyl, imidazole, imidazoline, oxazoline, oxazole, triazole,
thiazoline, thiazole, isothiazole, thiadiazoles, triazines,
isoxazole, oxindole, indoxyl, pyrazole, pyrazolone, pyrimidine,
pyrazine, quinoline, iosquinoline, and tetrazole groups. Preferred
heterocyclic groups formed with an oxygen atom include furan,
tetrahydrofuran, pyran, benzofurans, isobenzofurans, and
tetrahydropyran groups. Preferred heterocyclic groups formed with a
sulfur atom include thiophene, thianaphthene, tetrahydrothiophene,
tetrahydrothiapyran, and benzothiophenes.
[0060] As used herein, "hydroxyalkyl" groups are alkyl groups that
have a hydroxyl group appended thereto. As used herein,
"hydroxyalkoxy" groups are alkoxy groups that have a hydroxyl group
appended thereto. As used herein, "halogen" refers to fluorine,
chlorine, bromine and iodine.
[0061] As used herein, the term "amino acid" denotes a molecule
containing both an amino group and a carboxyl group. Embodiments of
amino acids include (t-amino acids; i.e., carboxylic acids of
general formula HOOC--CH(NH.sub.2)-(side chain). Side chains of
amino acids include naturally occurring and non-naturally occurring
moieties. Non-naturally occurring (i.e., unnatural) amino acid side
chains are moieties that are used in place of naturally occurring
amino acid side chains in, for example, amino acid analogs. See,
for example, Lehninger, Biochemistry, 2nd Ed., Worth Publishers,
Inc, 1975, pp. 73-75, incorporated by reference herein. As used
herein "Pro" denotes proline, "Ser" denotes Serine, "Gly" denotes
glycine, and "Lys" denotes lysine. In certain embodiments,
substituent groups for the compounds described herein include the
residue of an amino acid after removal of the hydroxyl moiety of
the carboxyl group thereof; i.e., groups of formula
--C(.dbd.O)CH(NH.sub.2)-(side chain).
[0062] The compounds of the invention may be present in various
forms as will be appreciated by the skilled artisan. Such forms
include, but are not limited to, pharmaceutically acceptable salts,
prodrugs, polymorphs, stereoisomers, and the like. As used herein,
the term "pharmaceutically acceptable" refers to those compounds,
materials, compositions, and/or dosage forms which are, within the
scope of sound medical judgment, suitable for contact with the
tissues of human beings and animals without excessive toxicity,
irritation, allergic response, or other problem complications
commensurate with a reasonable benefit/risk ratio.
[0063] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines;
alkali or organic salts of acidic residues such as carboxylic
acids; and the like. The pharmaceutically acceptable salts include
the conventional non-toxic salts or the quaternary ammonium salts
of the parent compound formed, for example, from non-toxic
inorganic or organic acids. For example, such conventional
non-toxic salts include those derived from inorganic acids such as
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric
and the like; and the salts prepared from organic acids such as
acetic, propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, sulfanilic,
2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane
disulfonic, oxalic, isethionic, and the like.
[0064] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical methods.
Generally, such salts can be prepared by reacting the free acid or
base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a
mixture of the two. Generally, nonaqueous media like ether, ethyl
acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
17th Ed., Mack Pub. Co., Easton, Pa., 1985, p. 1418, the disclosure
of which is hereby incorporated by reference.
[0065] "Effective amount" refers to an amount of a compound as
described herein that may be therapeutically effective to inhibit,
prevent or treat the symptoms of particular disease or disorder.
Such diseases and disorders include, but are not limited to, those
pathological conditions associated with uncontrolled cell growth.
Thus, for example, the term "effective amount", when used in
connection with the compounds of the present invention refers to
the treatment and/or prevention of uncontrolled cell growth.
[0066] "In combination with", "combination therapy" and
"combination products" refer, in certain embodiments, to the
concurrent administration to a patient of a trk tyrosine kinase
inhibitor and an antineoplastic agent, including, for example, the
compounds of formulas (I) and (II). When administered in
combination, each component may be administered at the same time or
sequentially in any order at different points in time. Thus, each
component may be administered separately but sufficiently closely
in time so as to provide the desired therapeutic effect. "Dosage
unit" refers to physically discrete units suited as unitary dosages
for the particular individual to be treated. Each unit may contain
a predetermined quantity of active compound(s) calculated to
produce the desired therapeutic effect(s) in association with the
required pharmaceutical carrier. The specification for the dosage
unit forms of the invention may be dictated by (a) the unique
characteristics of the active compound(s) and the particular
therapeutic effect(s) to be achieved, and (b) the limitations
inherent in the art of compounding such active compound(s).
[0067] "Patient" refers to animals, including mammals, preferably
humans.
[0068] The present invention provides methods and compositions that
may be useful for the treatment of cancer. More specifically, the
present invention is directed to methods and pharmaceutical
compositions comprising a combination of a trk tyrosine kinase
inhibitor and an antineoplastic agent. As noted above,
antineoplastic agents have been used in systemic chemotherapy and
have shown antitumor activity against a variety of solid tumors,
but the prognosis and overall survival of cancer patients
undergoing chemotherapy remains poor. In addition, anti-tumor
efficacy has been demonstrated for various trk tyrosine kinase
inhibitors. Chemotherapy with either antineoplastic agents, or trk
tyrosine kinase inhibitors, however, has not provided a desirable
increase in the survival of patients. Surprisingly, it has been
unexpectedly discovered that treatment with a combination of a trk
tyrosine kinase inhibitor and an antineoplastic agent, according to
the methods and compositions of the present invention, may
desirably and advantageously prolong survival. The enhanced
survival that may be achieved through combination therapy with a
trk tyrosine kinase inhibitor and an antineoplastic agent, as
described herein, may effectively be greater than a simple additive
effect of the two agents, when administered separately.
[0069] The present invention is directed to combination therapy for
the treatment of cancer. More specifically, the invention is
directed to methods for the treatment of cancer that involve the
administration of a combination of a trk tyrosine kinase inhibitor
and an antineoplastic agent. The invention is further directed to
compositions comprising a trk tyrosine kinase inhibitor and an
antineoplastic agent. The present combination methods and
compositions may be used to treat patients with cancer, and
preferably to significantly increase the survival of cancer
patients, relative to presently-available treatments.
[0070] The methods and compositions of the present invention may be
used to treat a wide variety of cancers, including, for example,
carcinomas of the pancreas, prostate, breast, thyroid, colon, and
lung; malignant melanomas; glioblastomas; neuroectodermal-derived
tumors including Wilm's tumor, neuroblastomas, and
medulloblastomas; and leukemias including, but not limited to,
acute myelogenous leukemia ("ALM"), chronic myelogenous leukemia
("CLM"), acute lymphocytic leukemia ("ALL"), and chronic
lymphocytic leukemia ("CLL"). Of these, the present methods and
compositions may preferably be used to treat carcinomas of the
prostate and pancreas, with carcinomas of the pancreas being
especially suitable for treatment. Exemplary of carcinomas of the
pancreas that may be treated with the present methods and
compositions is pancreatic ductal adenocarcinoma (PDAC).
[0071] Other carcinomas that may be treated with the methods and
compositions of the present invention, in addition to those
exemplified above, would be readily apparent to one of ordinary
skill in the art, once armed with the teachings of the present
disclosure.
[0072] As noted above, the methods and compositions of the present
invention involve a trk tyrosine kinase inhibitor. A wide variety
of trk tyrosine kinase inhibitors are available and may be suitable
for use in the methods and compositions of the present invention.
In preferred form, the trk tyrosine kinase inhibitor is an
indolocarbazole. In certain preferred embodiments, the trk tyrosine
kinase inhibitor is a compound of the following formula (I): 9
[0073] or a stereoisomer or pharmaceutically acceptable salt form
thereof, wherein:
[0074] (a) when Z.sup.1 and Z are both hydrogen:
[0075] (1) R is selected from the group consisting of OH, O-n-alkyl
of 1-6 carbons, and O-acyl of 2-6 carbons;
[0076] (2) X is selected from the group consisting of H;
CONHC.sub.6H.sub.5 with the proviso that both R.sup.1 and R.sup.2
are not Br; CH.sub.2Y wherein Y is:
[0077] OR.sup.7 wherein R.sup.7 is H or acyl of 2-5 carbons;
[0078] SOR.sup.8 wherein R is alkyl of 1-3 carbons, aryl, or a
heterocyclic group including a nitrogen atom;
[0079] NR.sup.9R.sup.10 wherein R.sup.9 and R.sup.10 are each
independently H, alkyl of 1-3 carbons, Pro, Ser, Gly, Lys, or acyl
of 2-5 carbons, with the proviso that only one of R.sup.9 and
R.sup.10 is Pro, Ser, Gly, Lys or acyl;
[0080] SR.sup.16 wherein R.sup.16 is an aryl, alkyl of 1-3 carbons
or a heterocyclic group that includes a nitrogen atom;
[0081] N.sub.3; CO.sub.2CH.sub.3; S-Glc;
[0082] CONR.sup.11R.sup.12 wherein R.sup.11 and R.sup.12 are each
independently H, alkyl of 1-6 carbons, CrH.sub.5, or hydroxyalkyl
of 1-6 carbons, or R.sup.1 and R.sup.12 are combined to form
--CH.sub.2CH.sub.2OCH.sub.2CH.sub.2--; CO.sub.2CH.sub.3;
CH.dbd.NNHCONH.sub.2; CONHOH; CH.dbd.NOH; 10
[0083] CH.dbd.NN(R.sup.17).sub.2 wherein R.sup.17 represents aryl;
CH.sub.2NHCONHR.sup.15 wherein R.sup.18 is lower alkyl or aryl;
or
[0084] X and R are combined together to form
--CH.sub.2NHCO.sub.2--, --CH.sub.2OC(CH.sub.3).sub.2O--, .dbd.O, or
--CH.sub.2N(CH.sub.3)CO.sub.2- --;
[0085] (3) each of R.sup.1, R.sup.2, R.sup.1and R.sup.6 is,
independently, H or up to two of them are F; Cl; Br; I; NO.sub.2;
CN; OH; NHCONHR.sup.13 wherein R.sup.13 is C.sub.6H.sub.5 or alkyl
of 1-3 carbons with the proviso that only one of R.sup.1, R.sup.2,
R.sup.5 and R.sup.6 is NHCONHR.sup.13; CH.sub.2OR.sup.13; alkyl of
1-3 carbons; CH.sub.2OCONHR.sup.14; or NHCO.sub.2R.sup.4; in which
R.sup.14 is lower alkyl; CH(SC.sub.6HS).sub.2 or
[0086] CH(--SCH.sub.2CH.sub.2S--); or R.sup.1 is
CH.sub.2S(O).sub.pR.sup.2- 1 where p=0 or 1, and R.sup.21 is aryl,
alkyl of 1-3 carbons, a heterocyclic group that includes a nitrogen
atom, 11
[0087] or CH.sub.2CH.sub.2N(CH.sub.3).sub.2, and R.sup.2, R.sup.5,
and R.sup.6 are H; or R.sup.1 is CH.dbd.NNR.sup.22R.sup.23, wherein
R.sup.22 and R.sup.23 are each independently H, alkyl of 1-3
carbons, C(.dbd.NH)NH.sub.2, or a heterocyclic group that includes
a nitrogen atom, or R.sup.22 and R.sup.23 are combined together to
form --(CH.sub.2).sub.4--, --(CH.sub.2CH.sub.2OCH.sub.2CH.sub.2)--,
or --(CH.sub.2CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2)--, with the
proviso that R.sup.22 and R.sup.23 cannot both be H, and at least
one of R.sup.22 or R.sup.23 is H, except when both are alkyl, and
R.sup.2, R.sup.5 and R.sup.6 are H;
[0088] and
[0089] (b) when Z.sup.1 and Z.sup.2 are both combined together to
represent 0; X is CO.sub.2CH.sub.3; R is OH and R.sup.1, R.sup.2,
R.sup.5 and R.sup.6 are each hydrogen.
[0090] In particularly preferred embodiments, the compound of
formula I has the following formula I-a: 12
[0091] where R, X, R.sup.1and R.sup.2 are as previously
described.
[0092] In preferred form, in the compounds of formula I-a,
R.sup.1and R.sup.2 are selected from H, alkyl, Cl, Br, CH.sub.2OH,
CH.sub.2SOCH.sub.2CH.sub.3, NHCONHC6H.sub.5,
CH.sub.2SCH.sub.2CH.sub.3, CH.sub.2SC.sub.6H.sub.5,
NIHCO.sub.2CH.sub.3, CH.sub.2OC(.dbd.O)NHCH.sub.- 2CH.sub.3,
CH.dbd.NNH, and CH.sub.2OCH.sub.2CH.sub.3; R is selected from OH
and OCH.sub.3; and X is selected from OH, CH.sub.2OH, and
CO.sub.2alkyl.
[0093] In even more preferred embodiments, the compound of formula
I-a is selected from: 13
[0094] In still more preferred embodiments, the compound of formula
(I-a) is: 14
[0095] In another preferred form, the trk tyrosine kinase inhibitor
is an indenocarbazole. In certain preferred embodiments, the trk
tyrosine kinase inhibitor is a compound of the following formula
(III): 15
[0096] or a stereoisomer or pharmaceutically acceptable salt form
thereof, wherein:
[0097] R.sup.1 is selected from the group consisting of:
[0098] a) H, substituted or unsubstituted C.sub.1-4 alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, or substituted
or unsubstituted heteroarylalkyl;
[0099] b) --C(.dbd.O)R.sup.9, where R.sup.9 is selected from the
group consisting of H, C.sub.1-4 alkyl, aryl and heteroaryl;
[0100] c) --OR.sup.10O, where R.sup.10 is selected from the group
consisting of H and C.sub.1-4 alkyl;
[0101] d) --C(.dbd.O)NH.sub.2, --NR.sup.11R.sup.12,
--(CH.sub.2).sub.pNR.sup.11R.sup.12, --(CH.sub.2).sub.pOR ,
--O(CU.sup.2).sub.pOR and --O(CH.sub.2).sub.pNR.sup.11R.sup.12,
wherein p is from 1 to 4; and wherein either
[0102] 1) R.sup.11 and R.sup.12 are each independently selected
from the group consisting of H and C.sub.1-4 alkyl; or
[0103] 2) R.sup.11 and R.sup.12 together form a linking group of
the formula --(CH.sub.2).sub.2--X.sup.1--(CH.sub.2).sub.2--,
wherein X.sup.1 is selected from the group consisting of --O--,
--S--, and --CH.sub.2--;
[0104] R.sup.2 is selected from the group consisting of H,
C.sub.1-4 alkyl, --OH, and C.sub.1-4 alkoxy;
[0105] R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently
selected from the group consisting of:
[0106] a) H, aryl, heteroaryl, F, Cl, Br, I, --CN, CF.sub.3,
--NO.sub.2, --OH, --OR ,
--O(CH.sub.2).sub.pNR.sup.11R.sup.12--OC(.dbd.O)R.sup.9,
--OC(.dbd.O)NR.sup.2R.sup.7, --OC(.dbd.O)NR.sup.11R.sup.12,
--O(CH.sub.2).sub.pOR.sup.10, --CH.sub.2OR.sup.10,
--NR.sup.11R.sup.12, --NR.sup.10S(.dbd.O).sub.2R.sup.9,
NR.sup.10C(.dbd.O)R.sup.9;
[0107] b) --CH.sub.2OR.sup.14, wherein R.sup.14 is the residue of
an amino acid after the hydroxyl group of the carboxyl group is
removed;
[0108] c) --NROC(.dbd.O)NR.sup.11R.sup.12, --CO.sub.2R.sup.2,
--C(.dbd.O)R.sup.2, --C(.dbd.O)NR.sup.11R.sup.12,
--CH.dbd.NOR.sup.2, --CH.dbd.NR.sup.9,
--(CH.sub.2).sub.pNR.sup.11R.sup.12, --(CH.sub.2).sub.pNHR.sup.14,
or --CH.dbd.NNR.sup.2R.sup.2A wherein R.sup.2A is the same as
R.sup.2;
[0109] d) --S(O).sub.yR.sup.2--(CH.sub.2).sub.pS(O).sub.yR.sup.9,
--CH.sub.2S(O).sub.yR.sup.14 wherein y is 0, 1 or 2;
[0110] e) C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
wherein each alkyl, alkenyl, or alkynyl group may substituted with
1 to 3 groups selected from the group consisting of:
[0111] C.sub.6-10 arylalkyl, heteroaryl, arylalkoxy,
heterocycloalkoxy, hydroxyalkoxy, alkyloxy-alkoxy,
hydroxyalkylthio, alkoxy-alkylthio, F, Cl, Br, I, --CN, --NO.sub.2,
--OH, --OR.sup.9, --X.sup.2(CH.sub.2),NR IR.sup.1,
--X.sup.2(CH.sub.2).sub.pC(.dbd.O)NR.sup.11R.sup.12,
--X.sup.2(CH.sub.2).sub.pOC(.dbd.O)NR.sup.11R.sup.12, --X.sup.2
(CH.sub.2).sub.pCO.sub.2R.sup.9,
--X.sup.2(CH.sub.2).sub.pS(O).sub.yR.sup- .9,
--X.sup.2(CH.sub.2).sub.pNR.sup.11C(.dbd.O)NR.sup.11R.sup.12,
--OC(.dbd.O)R.sup.9, _OCONHR.sup.2, --O-tetrahydropyranyl,
--NR.sup.11R.sup.12, --NR.sup.10C(.dbd.O)R.sup.9,
--NR.sup.10CO.sub.2R.su- p.9, --NR.sup.10C(.dbd.O)NR.sup.11R.sup.2,
--NHC(.dbd.NH)NH.sub.2, NR.sup.10S(O).sub.2R.sup.9,
--S(O).sub.yR.sup.9, --CO.sub.2R.sup.2,
--C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)R.sup.2,
--CH.sub.2OR.sup.10, --CH.dbd.NNR.sup.2R.sup.2A,
--CH.dbd.NOR.sup.2, --CH.dbd.NR.sup.9,
--CH.dbd.NNHCH(N.dbd.NH)NH.sub.2,
--S(.dbd.O).sub.2NR.sup.2R.sup.2A, --P(.dbd.O)(OR.sup.10).sub.2,
--OR.sup.14, and a monosaccharide having from 5 to 7 carbons
wherein each hydroxyl group of the monosaccharide is independently
either unsubstituted or is replaced by H, C.sub.1-4 alkyl,
alkylcarbonyloxy having from 2 to 5 carbons, or C.sub.1-4
alkoxy;
[0112] wherein X.sup.2 is O, S, or NRO;
[0113] R.sup.7 and R.sup.8 are each independently selected from the
group consisting of H, C.sub.1-4 alkyl, C.sub.1-4 alkoxy,
substituted or unsubstituted C.sub.6-10 arylalkyl, substituted or
unsubstituted heteroarylalkyl, --(CH.sub.2).sub.pOR.sup.10,
--(CH.sub.2).sub.pOC(.dbd.O- )NR.sup.11R.sup.12, and
--(CH.sub.2).sub.pNR.sup.11R.sup.12;
[0114] or R.sup.7 and R.sup.8 together form a linking group of the
formula --CH.sub.2--X.sup.3--CH.sub.2--; wherein X.sup.3 is X.sup.2
or a bond;
[0115] m and n are each independently 0, 1, or 2;
[0116] Y is selected from the group consisting of --O--, --S--,
--N(R.sup.10)--, --N.sup.+(O.sup.-)(R.sup.10)--, --N(OR.sup.10)--,
and --CH.sub.2--;
[0117] Z is selected from the group consisting of a bond, --O--,
--CH.dbd.CH--, --S--, --C(.dbd.O)--, --CH(OR.sup.10)--,
--N(R.sup.10)--, --N(OR.sup.10)--, CH(NR.sup.11R.sup.12)--,
--C(.dbd.O)N(R.sup.17)--, --N(R.sup.17)C(.dbd.O)--,
--N(S(O).sub.yR.sup.9)--, --N(S(O).sub.yNR.sup.11R.sup.12)--,
--N(C(.dbd.O)R.sup.17)--, --C(R.sup.15R.sup.16)--,
--N.sup.+(O.sup.-)(R.sup.10)--, --CH(OH)--CH(OH)--, and
--CH(O(C.dbd.O)R.sup.9)CH(OC(.dbd.O)R.sup.9A)--;
[0118] wherein
[0119] R.sup.9A is the same as R.sup.9;
[0120] R.sup.15 and R.sup.16 are independently selected from the
group consisting of H, --OH, --C(.dbd.O)R.sup.10,
--O(C.dbd.O)R.sup.9, hydroxyalkyl, and --CO.sub.2R.sup.10;
[0121] R.sup.17 is selected from the group consisting of H,
C.sub.1-6 alkyl, aryl, and heteroaryl;
[0122] A.sup.1 and A.sup.2 are selected from the group consisting
of H, H; H, OR.sup.2; H, --SR.sup.2; H, --N(R.sup.2).sub.2; and a
group wherein A.sup.1 and A.sup.2 together form a moiety selected
from the group consisting of .dbd.O, .dbd.S, and .dbd.NR.sup.2. In
particularly preferred embodiments, the compound of formula (M) has
the following formula (III-a): 16
[0123] or a stereoisomer or pharmaceutically acceptable salt form
thereof, wherein:
[0124] R.sup.1 is H or substituted or unsubstituted C.sub.1-4
alkyl;
[0125] R.sup.2 is selected from the group consisting of H,
C.sub.1-4 alkyl, --OH, and C.sub.1-4 alkoxy;
[0126] R.sup.3 and R.sup.5 are each independently selected from the
group consisting of:
[0127] a) H, aryl, heteroaryl, F, Cl, Br, I, --CN, CF.sub.3,
--NO.sub.2, --OH, --OR.sup.9, --O(CH.sub.2).sub.pNR.sup.11R.sup.12,
--OC(.dbd.O)R.sup.9, --OC(.dbd.O)NR.sup.11R.sup.12,
--OC(.dbd.O)NR.sup.11R.sup.12, --O(CH.sub.2).sub.pOR.sup.10,
--CH.sub.2OR.sup.10, --NR.sup.11R.sup.12,
--NR.sup.10S(.dbd.O).sub.2R.sup- .9, NR.sup.10C(.dbd.O)R.sup.9;
[0128] b) --CH.sub.2OR.sup.14, wherein R.sup.14 is the residue of
an amino acid after the hydroxyl group of the carboxyl group is
removed;
[0129] c) --NR.sup.10C(.dbd.O)NR.sup.11R.sup.12, --CO.sub.2R.sup.2,
--C(.dbd.O)R.sup.2, --C(.dbd.O)NR.sup.11R.sup.12,
--CH.dbd.NOR.sup.2, --CH.dbd.NR.sup.9,
--(CH.sub.2).sub.pNR.sup.11R.sup.12, --(CH.sub.2)NH.sup.4, or
--CH.dbd.NNR.sup.2R.sup.2A; wherein R.sup.2A is the same as
R.sup.2;
[0130] d) --S(O).sub.yR.sup.2--(CH.sub.2).sub.pS(O).sub.yR.sup.9,
--CH.sub.2S(O).sub.yR.sup.14 wherein y is 0, 1 or 2;
[0131] e) C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
wherein each alkyl, alkenyl, or alkynyl group may substituted with
1 to 3 groups selected from the group consisting of:
[0132] C.sub.6-10 arylalkyl, heteroaryl, arylalkoxy,
heterocycloalkoxy, hydroxyalkoxy, alkyloxy-alkoxy,
hydroxyalkylthio, alkoxyalkylthio, F, Cl, Br, I, --CN, --NO.sub.2,
--OH, --OR.sup.9, --X.sup.2(CH.sub.2).sub.pNR.su- p.1R ,
--X.sup.2(CH.sub.2).sub.pC(.dbd.O)NR.sup.11R.sup.12,
--X.sup.2(CH.sub.2).sub.pOC(.dbd.O)NR.sup.11R.sup.12,
--X.sup.2(CH.sub.2).sub.pCO.sub.2R.sup.9,
--X.sup.2(CH.sub.2).sub.pS(O).s- ub.yR.sup.9,
--X.sup.2(CH.sub.2).sub.pNR.sup.10C(.dbd.O)NR.sup.11R.sup.12,
--OC(.dbd.O)R , --OCONHR.sup.2, --O-tetrahydropyranyl,
--NR.sup.11R.sup.12, --NR.sup.10C(.dbd.O)R.sup.9,
--NR.sup.10CO.sub.2R.su- p.9,
NR.sup.10C.(.dbd.O)NR.sup.11R.sup.12--NHC(.dbd.NH)NH.sub.2,
NR.sup.10S(O).sub.2R.sup.9, --S(O).sub.yR.sup.9,
CO.sub.2R.sup.2--C(.dbd.- O)NR.sup.11R.sup.12, --C(.dbd.O)R.sup.2,
--CH.sub.2OR.sup.10, --CH.dbd.NNR.sup.2R.sup.2A,
--CH.dbd.NOR.sup.2, --CH.dbd.NR.sup.9,
--CH.dbd.NNHCH(N.dbd.NH)NH.sub.2,
--S(.dbd.O).sub.2NR.sup.2R.sup.2A, --P(.dbd.O)(OR.sup.10).sub.2,
--OR.sup.14, and a monosaccharide having from 5 to 7 carbons
wherein each hydroxyl group of the monosaccharide is independently
either unsubstituted or is replaced by H, C.sub.1-4 alkyl,
alkylcarbonyloxy having from 2 to 5 carbons, or C.sub.1-4 alkoxy;
wherein
[0133] X.sup.2 is O, S, or NR.sup.10;
[0134] R.sup.9 and R.sup.10 are each independently H or C.sub.1-4
alkyl;
[0135] R.sup.11 and R.sup.12 are each independently H or C.sub.1-4
alkyl; or R.sup.11 and R.sup.12 together form a linking group of
the formula --(CH.sub.2).sub.2--X.sup.1--(CH.sub.2).sub.2--,
wherein X.sup.1 is selected from the group consisting of --O--,
--S--, and --CH.sub.2--; and
[0136] p is from 1 to 4,
[0137] R.sup.7 and R.sup.8 are each independently H or substituted
or unsubstituted C.sub.1-4 alkyl; R.sup.15 and R.sup.16 are
independently selected from the group consisting of H, --OH,
--C(.dbd.O)R.sup.10, --O(C.dbd.O)R.sup.9, hydroxyalkyl, and
--CO.sub.2R.sup.10.
[0138] In a preferred embodiment, the compound of formula (III-a)
is: 17
[0139] Other trk tyrosine kinase inhibitors that may be employed in
the methods and compositions of the present invention, in addition
to those exemplified above, would be readily apparent to one of
ordinary skill in the art, once armed with the teachings of the
present disclosure.
[0140] As noted above, the methods and compositions of the present
invention further involve an antineoplastic agent. A wide variety
of antineoplastic agents are available and may be suitable for use
in the methods and compositions of the present invention. In
preferred embodiments, the antineoplastic agent is selected from
fluoropyrimidines, pyrimidine nucleosides and purines. In more
preferred embodiments, the fluoropyrimidine is selected from
5-fluorouracil and ftorafur, the pyrimidine nucleoside is selected
from gemcitabine, 5-azacytidine and cytosine arabinoside, and the
purine is 6-thioguanine.
[0141] In preferred embodiments, the antineoplastic agent is a
compound of the following formula (II): 18
[0142] or a pharmaceutically acceptable salt form thereof,
wherein:
[0143] R.sup.24 is selected from H and --C(.dbd.O)--R.sup.28;
[0144] R.sup.25 is a base defined by one of the following formulae:
19
[0145] X' is selected from N and C--R.sup.27;
[0146] R.sup.26 is selected from H, alkyl and
--C(.dbd.O)--R.sup.28;
[0147] R.sup.27 is selected from H, alkyl, amino, bromo, fluoro,
chloro and iodo; and
[0148] R.sup.28 is selected from H and alkyl;
[0149] and a pharmaceutically acceptable carrier.
[0150] In particularly preferred embodiments, R.sup.25 of formula
(II) is a base of the following formula 20
[0151] where X' and R.sup.26 are as previously described.
[0152] In preferred form, X' of the above formula is C--R.sup.27.
In more preferred embodiments, R.sup.24, R.sup.26, R.sup.27 and
R.sup.28 are H. An even more preferred antineoplastic agent for use
in the present methods and compositions is gemcitabine, i.e., the
compound of the following formula: 21
[0153] Thus, in particularly preferred form, the methods and
compositions of the present invention involve a trk tyrosine kinase
inhibitor of the following formula (I-a-ii): 22
[0154] and an antineoplastic agent of the following formula (II-a):
23
[0155] Thus, in another particularly preferred form, the methods
and compositions of the present invention involve a trk tyrosine
kinase inhibitor of the following formula (III-a-i): 24
[0156] and an antineoplastic agent of the following formula (11-a):
25
[0157] In more preferred embodiments, the methods and compositions
of the present invention involve a trk tyrosine kinase inhibitor of
formula (I-a-ii) and an antineoplastic agent of formula (11-a) for
the treatment of pancreatic cancer, and particularly for the
treatment of pancreatic ductal adenocarcinoma.
[0158] In other more preferred embodiments, the methods and
compositions of the present invention involve a trk tyrosine kinase
inhibitor of formula (II-a) and an antineoplastic agent of formula
(II-a) for the treatment of pancreatic cancer, and particularly for
the treatment of pancreatic ductal adenocarcinoma.
[0159] In certain preferred embodiments of the invention, the
antineoplastic agent is administered to the patient in a
substantial excess relative to the trk tyrosine kinase inhibitor.
The term "substantial excess", as used herein, means that the
antineoplastic agent is preferably administered in an amount of at
least twice as much, on a weight basis, relative to the trk
tyrosine kinase inhibitor. In more preferred embodiments, the
antineoplastic agent and the trk tyrosine kinase inhibitor are
administered to the patient in a weight ratio of from about 2:1 to
about 50:1, more preferably from about 4:1 to about 20:1, and even
more preferably from about 8:1 to about 16:1.
[0160] By way of general guidance, the daily dosage of the
antineoplastic agent, when used for the indicated effects, will
range from about 1 mg/kg to about 300 mg/kg (and all combinations
and subcombinations of ranges and specific dosages therein),
preferably from about 10 mg/kg to about 200 mg/kg, and more
preferably from about 50 mg/kg to about 150 mg/kg. The dosage units
for the antineoplastic agent of the method may alternatively be
expressed as mg/mm.sup.2; accordingly, in a preferred embodiment
the antineoplastic agent may be administered in an amount which
ranges from about 30 mg/mm.sup.2 to about 900 mg/mm.sup.2 (and all
combinations and subcombinations of ranges and specific dosages
therein), and more preferably from about 150 mg/mm.sup.2 to about
600 mg/mm.sup.2, and even more preferably from about 210
mg/mm.sup.2 to about 450 mg/mm.sup.2.
[0161] Also by way of general guidance, the daily dosage of the trk
tyrosine kinase inhibitor may range from about 1 mg/kg to about 200
mg/kg (and all combinations and subcombinations of ranges and
specific dosages therein), preferably from about 2 mg/kg to about
100 mg/kg, and more preferably from about 5 mg/kg to about 50
mg/kg.
[0162] In connection with the compositions of the present
invention, the antineoplastic agent is preferably present in the
compositions in a substantial excess relative to the trk tyrosine
kinase inhibitor. In certain preferred embodiments, the
antineoplastic agent and the trk tyrosine kinase inhibitor are
present in the compositions in a weight ratio of from about 2:1 to
about 50: 1, more preferably from about 4:1 to about 20:1, and most
preferably from about 8:1 to about 16:1.
[0163] In certain preferred embodiments, the compositions are in a
single dosage unit form.
[0164] Another embodiment of the invention includes pharmaceutical
kits comprising one or more containers containing pharmaceutical
dosage units comprising an effective amount of a trk tyrosine
kinase inhibitor in combination with an effective amount of an
antineoplastic agent.
[0165] In certain preferred embodiments, the kits further
comprising conventional pharmaceutical kit components.
[0166] The compounds employed in the methods of the present
invention may exist in prodrug form. As used herein, "prodrug" is
intended to include any covalently bonded carriers which release
the active parent drug, for example, as according to formulas (I)
or (II) or other formulas or compounds employed in the methods of
the present invention in vivo when such prodrug is administered to
a mammalian subject. Since prodrugs are known to enhance numerous
desirable qualities of pharmaceuticals (e.g., solubility,
bioavailability, manufacturing, etc.) the compounds employed in the
present methods may, if desired, be delivered in prodrug form.
Thus, the present invention contemplates methods of delivering
prodrugs. Prodrugs of the compounds employed in the present
invention, for example formula (I), may be prepared by modifying
functional groups present in the compound in such a way that the
modifications are cleaved, either in routine manipulation or in
vivo, to the parent compound.
[0167] Accordingly, prodrugs include, for example, compounds
described herein in which a hydroxy, amino, or carboxy group is
bonded to any group that, when the prodrug is administered to a
mammalian subject, cleaves to form a free hydroxyl, free amino, or
carboxylic acid, respectively. Examples include, but are not
limited to, acetate, formate and benzoate derivatives of alcohol
and amine functional groups; and alkyl, carbocyclic, aryl, and
arylalkyl esters such as methyl, ethyl, propyl, iso-propyl, butyl,
isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and
phenethyl esters, and the like.
[0168] The compounds of the present invention may be prepared in a
number of ways well known to those skilled in the art. The
compounds can be synthesized, for example, by the methods described
below, or variations thereon as appreciated by the skilled artisan.
All processes disclosed in association with the present invention
are contemplated to be practiced on any scale, including milligram,
gram, multigram, kilogram, multikilogram or commercial industrial
scale.
[0169] It will be appreciated that the compounds of the present
invention may contain one or more asymmetrically substituted carbon
atoms, and may be isolated in optically active or racemic forms.
Thus, all chiral, diastereomeric, racemic forms and all geometric
isomeric forms of a structure are intended, unless the specific
stereochemistry or isomeric form is specifically indicated. It is
well known in the art how to prepare and isolate such optically
active forms. For example, mixtures of stereoisomers may be
separated by standard techniques including, but not limited to,
resolution of racemic forms, normal, reverse-phase, and chiral
chromatography, preferential salt formation, recrystallization, and
the like, or by chiral synthesis either from chiral starting
materials or by deliberate synthesis of target chiral centers.
[0170] As will be readily understood, functional groups present may
contain protecting groups during the course of synthesis.
Protecting groups are known per se as chemical functional groups
that can be selectively appended to and removed from
functionalities, such as hydroxyl groups and carboxyl groups. These
groups are present in a chemical compound to render such
functionality inert to chemical reaction conditions to which the
compound is exposed. Any of a variety of protecting groups may be
employed with the present invention. Preferred protecting groups
include the benzyloxycarbonyl (Cbz; Z) group and the
tert-butyloxycarbonyl (13oc) group. Other preferred protecting
groups according to the invention may be found in Greene, T. W. and
Wuts, P. G. M., Protective Groups in Organic Synthesis 2nd Ed.,
Wiley & Sons, 1991.
[0171] Indolocarbazoles may be synthesized by methods taught, for
example, in U.S. Pat. Nos. 4,923,986; 4,877,776; 5,093,330;
5,461,146; 5,468,872; 5,621,100; 5,621,101; 5,516,771; and
5,599,808; and PCT publication Nos. WO 93/08809 and WO 97/46565,
the discloses of which are hereby incorporated herein by reference
in their entireties. Additional methods of preparation are set
forth in Moody et al., J. Org. Chem. 57:2105-2114, 1992, also
incorporated herein by reference.
[0172] Indenocarbazoles may be synthesized by methods taught, for
example, in U.S. Pat. No. 6,127,401, the disclosure of which is
hereby incorporated herein by reference in its entirety.
[0173] Antineoplastic agents useful in the invention may be
synthesized by methods known in the art. The compounds of formula
(II) may be synthesized by the methods taught, for example, in U.S.
Pat. Nos. 4,808,614 and 5,464,826, the disclosures of which are
hereby incorporated herein by reference in their entireties.
[0174] The compounds employed in the methods of the present
invention including, for example, antineoplastic agents and trk
tyrosine kinase inhibitors, may be administered by any means that
results in the contact of the active agents with the agents' site
or site(s) of action in the body of a patient. The compounds may be
administered by any conventional means available for use in
conjunction with pharmaceuticals, either as individual therapeutic
agents or in a combination of therapeutic agents. For example, they
may be administered as the sole active agents in a pharmaceutical
composition, or they can be used in combination with other
therapeutically active ingredients.
[0175] The compounds are preferably combined with a pharmaceutical
carrier selected on the basis of the chosen route of administration
and standard pharmaceutical practice as described, for example, in
Remington's Pharmaceutical Sciences, 17th Ed., Mack Pub. Co.,
Easton, Pa., 1985, the disclosures of which are hereby incorporated
herein by reference, in their entirety.
[0176] Compounds of the present invention can be administered to a
mammalian host in a variety of forms adapted to the chosen route of
administration, e.g., orally or parenterally. Parenteral
administration in this respect includes administration by the
following routes: intravenous, intramuscular, subcutaneous,
intraocular, intrasynovial, transepithelial including transdermal,
ophthalmic, sublingual and buccal; topically including ophthalmic,
dermal, ocular, rectal and nasal inhalation via insufflation,
aerosol and rectal systemic.
[0177] The active compound may be orally administered, for example,
with an inert diluent or with an assimilable edible carrier, or it
may be enclosed in hard or soft shell gelatin capsules, or it may
be compressed into tablets, or it may be incorporated directly with
the food of the diet. For oral therapeutic administration, the
active compound may be incorporated with excipient and used in the
form of ingestible tablets, buccal tablets, troches, capsules,
elixirs, suspensions, syrups, wafers, and the like. The amount of
active compound(s) in such therapeutically useful compositions is
preferably such that a suitable dosage will be obtained. Preferred
compositions or preparations according to the present invention may
be prepared so that an oral dosage unit form contains from about
0.1 to about 1000 mg of active compound.
[0178] The tablets, troches, pills, capsules and the like may also
contain one or more of the following: a binder, such as gum
tragacanth, acacia, corn starch or gelatin; an excipient, such as
dicalcium phosphate; a disintegrating agent, such as corn starch,
potato starch, alginic acid and the like; a lubricant, such as
magnesium stearate; a sweetening agent such as sucrose, lactose or
saccharin; or a flavoring agent, such as peppermint, oil of
wintergreen or cherry flavoring. When the dosage unit form is a
capsule, it may contain, in addition to materials of the above
type, a liquid carrier. Various other materials may be present as
coatings or to otherwise modify the physical form of the dosage
unit. For instance, tablets, pills, or capsules may be coated with
shellac, sugar or both. A syrup or elixir may contain the active
compound, sucrose as a sweetening agent, methyl and propylparabens
as preservatives, a dye and flavoring, such as cherry or orange
flavor. Of course, any material used in preparing any dosage unit
form is preferably pharmaceutically pure and substantially
non-toxic in the amounts employed. In addition, the active compound
may be incorporated into sustained-release preparations and
formulations.
[0179] The active compound may also be administered parenterally or
intraperitoneally. Solutions of the active compounds as free bases
or pharmacologically acceptable salts can be prepared in water
suitably mixed with a surfactant, such as hydroxypropylcellulose. A
dispersion can also be prepared in glycerol, liquid polyethylene
glycols and mixtures thereof and in oils. Under ordinary conditions
of storage and use, these preparations may contain a preservative
to prevent the growth of microorganisms.
[0180] The pharmaceutical forms suitable for injectable use
include, for example, sterile aqueous solutions or dispersions and
sterile powders for the extemporaneous preparation of sterile
injectable solutions or dispersions. In all cases, the form is
preferably sterile and fluid to provide easy syringability. It is
preferably stable under the conditions of manufacture and storage
and is preferably preserved against the contaminating action of
microorganisms such as bacteria and fungi. The carrier may be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (for example, glycerol, propylene glycol, liquid
polyethylene glycol and the like), suitable mixtures thereof, and
vegetable oils. The proper fluidity can be maintained, for example,
by the use of a coating, such as lecithin, by the maintenance of
the required particle size in the case of a dispersion, and by the
use of surfactants. The prevention of the action of microorganisms
may be achieved by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal
and the like. In many cases, it will be preferable to include
isotonic agents, for example, sugars or sodium chloride. Prolonged
absorption of the injectable compositions may be achieved by the
use of agents delaying absorption, for example, aluminum
monostearate and gelatin.
[0181] Sterile injectable solutions may be prepared by
incorporating the active compounds in the required amounts, in the
appropriate solvent, with various of the other ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions may be prepared by incorporating the
sterilized active ingredient into a sterile vehicle which contains
the basic dispersion medium and the required other ingredients from
those enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation may include vacuum drying and the freeze drying
technique which yield a powder of the active ingredient, plus any
additional desired ingredient from the previously sterile-filtered
solution thereof.
[0182] The therapeutic compounds of this invention may be
administered to a patient alone or in combination with a
pharmaceutically acceptable carrier. As noted above, the relative
proportions of active ingredient and carrier may be determined, for
example, by the solubility and chemical nature of the compounds,
chosen route of administration and standard pharmaceutical
practice.
[0183] The dosage of the compounds of the present invention that
will be most suitable for prophylaxis or treatment will vary with
the form of administration, the particular compound chosen and the
physiological characteristics of the particular patient under
treatment. Generally, small dosages may be used initially and, if
necessary, increased by small increments until the desired effect
under the circumstances is reached. Generally speaking, oral
administration may require higher dosages.
[0184] The combination products of the invention, such as
pharmaceutical compositions comprising an antineoplastic agent and
a trk tyrosine kinase inhibitor, may be in any dosage form, such as
those described herein, and can also be administered in various
ways, as described herein. In a preferred embodiment, the
combination products of the invention are formulated together, in a
single dosage form (that is, combined together in one capsule,
tablet, powder, or liquid, etc.). When the combination products are
not formulated together in a single dosage form, the antineoplastic
agent and the trk tyrosine kinase inhibitor may be administered at
the same time (that is, together), or at different times. When not
administered at the same time, preferably the administration of the
antineoplastic agent and the trk tyrosine kinase inhibitor occurs
less than about one hour apart, more preferably less than about 30
minutes apart, even more preferably less than about 15 minutes
apart, and still more preferably less than about 5 minutes apart.
Alternatively, the antineoplastic agent and the trk tyrosine kinase
inhibitor may be administered at different times that occur one or
more hours, or even days, apart.
[0185] Preferably, administration of the combination products of
the invention is oral, although other routes of administration, as
described above, are contemplated to be within the scope of the
present invention. Although it is preferable that the
antineoplastic agent and the trk tyrosine kinase inhibitor are both
administered in the same fashion (that is, for example, both
orally), if desired, they may each be administered in different
fashions (that is, for example, one component of the combination
product may be administered orally, and another component may be
administered intravenously). The dosage of the combination products
of the invention may vary depending upon various factors such as
the pharmacodynamic characteristics of the particular agent and its
mode and route of administration, the age, health and weight of the
recipient, the nature and extent of the symptoms, the kind of
concurrent treatment, the frequency of treatment, and the effect
desired.
[0186] The proper dosage of the combination products of this
invention will be readily ascertainable by one skilled in the art,
once armed with the present disclosure. With regard to a typical
dosage form of this type of combination product, such as a tablet,
the antineoplastic agent generally may be present in an amount
which ranges from about 10 to about 200 milligrams (and all
combinations and subcombinations of ranges and specific dosages
therein), and the trk tyrosine kinase inhibitor generally may be
present in an amount which ranges from about 0.5 to about 100
milligrams (and all combinations and subcombinations of ranges and
specific dosages therein).
[0187] Particularly when provided as a single dosage form, the
potential exists for a chemical interaction between the combined
active ingredients (for example, the antineoplastic agent and trk
tyrosine kinase inhibitor). For this reason, the preferred dosage
forms of the combination products of this invention are formulated
such that although the active ingredients are combined in a single
dosage form, the physical contact between the active ingredients is
minimized (that is, reduced).
[0188] In order to minimize contact, one embodiment of the
invention where the product is orally administered provides for a
combination product wherein one active ingredient is enteric
coated. By enteric coating one or more of the active ingredients,
it is possible not only to minimize the contact between the
combined active ingredients, but also, it is possible to control
the release of one of these components in the gastrointestinal
tract such that one of these components is not released in the
stomach but rather is released in the intestines. Another
embodiment of this invention where oral administration is desired
provides for a combination product wherein one of the active
ingredients is coated with a sustained-release material which
effects a sustained-release throughout the gastrointestinal tract
and also serves to minimize physical contact between the combined
active ingredients. Furthermore, the sustained-released component
can be additionally enteric coated such that the release of this
component occurs only in the intestine. Still another approach
would involve the formulation of a combination product in which the
one component is coated with a sustained and/or enteric release
polymer, and the other component is also coated with a polymer such
as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) or
other appropriate materials as known in the art, in order to
further separate the active components. The polymer coating serves
to form an additional barrier to interaction with the other
component.
[0189] Dosage forms of the combination products of the present
invention wherein one active ingredient is enteric coated can be in
the form of tablets such that the enteric coated component and the
other active ingredient are blended together and then compressed
into a tablet or such that the enteric coated component is
compressed into one tablet layer and the other active ingredient is
compressed into an additional layer. Optionally, in order to
further separate the two layers, one or more placebo layers may be
present such that the placebo layer is between the layers of active
ingredients. In addition, dosage forms of the present invention can
be in the form of capsules wherein one active ingredient is
compressed into a tablet or in the form of a plurality of
microtablets, particles, granules or non-perils, which are then
enteric coated. These enteric coated microtablets, particles,
granules or non-perils are then placed into a capsule or compressed
into a capsule along with a granulation of the other active
ingredient.
[0190] These as well as other ways of minimizing contact between
the components of combination products of the present invention,
whether administered in a single dosage form or administered in
separate forms but at the same time by the same manner, will be
readily apparent to those skilled in the art, once armed with the
present disclosure.
[0191] Pharmaceutical kits useful in, for example, the treatment of
cancer, which comprise a therapeutically effective amount of an
antineoplastic agent along with a therapeutically effective amount
of a trk tyrosine kinase inhibitor, in one or more sterile
containers, are also within the ambit of the present invention.
Sterilization of the container may be carried out using
conventional sterilization methodology well known to those skilled
in the art. The sterile containers of materials may comprise
separate containers, or one or more multi-part containers, as
exemplified by the UNIVIAL two-part container (available from
Abbott Labs, Chicago, Ill.), as desired. The antineoplastic agent
and the trk tyrosine kinase inhibitor may be separate, or combined
into a single dosage form as described above. Such kits may further
include, if desired, one or more of various conventional
pharmaceutical kit components, such as for example, one or more
pharmaceutically acceptable carriers, additional vials for mixing
the components, etc., as will be readily apparent to those skilled
in the art. Instructions, either as inserts or as labels,
indicating quantities of the components to be administered,
guidelines for administration, and/or guidelines for mixing the
components, may also be included in the kit.
[0192] The materials, methods, and examples presented herein are
intended to be illustrative, and not intended to limit the scope of
the invention. All publications, patent applications, patents, and
other references mentioned herein are incorporated by reference in
their entirety. Unless otherwise defined, all technical and
scientific terms are intended to have their art-recognized
meanings.
EXAMPLES
[0193] The invention is further demonstrated in the following
examples. All of the examples are actual examples. The examples are
for purposes of illustration and are not intended to limit the
scope of the present invention.
Example 1
Formulations
[0194] The compound of formula (I-a-ii) was formulated at 3.44
mg/mil in a vehicle of 40% polyethylene glycol (PEG) 1000
(Spectrum, Los Angeles, Calif.), 10% povidone C30 (ISP, Boudbrook,
N.J.), and 2% benzyl alcohol (Specturm, Los Angeles, Calif.) in
sterile injectable water.
[0195] Gemcitabine HCl (Gemzar) was obtained from Eli Lilly and Co.
(Indianapolis, Ind.) as a sterile, lyophilized powder formulated
with mannitol and sodium acetate, and resuspended to a
concentration of 1.0 mg/ml with 0.9% sodium chloride, pH 7.0.
Solutions of gemcitabine were freshly prepared for each day of
dosing and filter sterilized prior to administration.
Example 2
Tumor Xenograft Preparation
[0196] Human pancreatic ductal adenocarcinoma (PDAC) xenografts
were obtained from the left flanks of nude mice that had been
injected with 2.times.10.sup.6 Colo-357 human pancreatic carcinoma
cells. Colo-357 human PDAC cells were obtained from the American
Type Culture Collection (ATCC) and grown to subconfluency in
Minimal Essential Medium supplemented with 10% fetal bovine serum
and 1% penicillin/streptomycin. Cells were MAP and mycoplasma
tested by a commercial laboratory (Bio Reliance Corp.) prior to
use. Xenograft tumors were harvested and carefully sectioned into
2.times.2 mm.sup.2 fragments in a laminar flow hood using sterile
technique (PNAS 89:5645-49, 1992; Cancer Res. 55:4670-75, 1995).
Netrotic areas of the tumors were removed and discarded. The
2.times.2 mm tumor tissue fragments were then placed in sterile,
undiluted Matrigel and ice for 60 minutes prior to implantation.
(Cancer Res. 55:4670-75, 1995).
Example 3
Orthotopic PDAC Model Development
[0197] At approximately 8 weeks of age female nu/nu mice were
anesthetized with a mixture of ketamine/xylazine given by IM
injection. Following establishment of satisfactory anesthesia, a
left lateral laparotomy was performed using aseptic technique, and
the spleen and pancreas exteriorized by gentle traction. Two of the
2.times.2 mm.sup.2 tumor xenograft fragments prepared as described
above were anchored to the posterior surface of the splenic portion
of the pancreas of each mouse with a 6-0 Prolene suture (Cancer
Res. 56:5713-19, 1996; J. Surg. Oncol. 40:261-265, 1989). The
abdominal incision was closed with 6-0 Vicryl and the skin closed
with skin staples. Mice were observed daily for any signs of
infection of the incision line and, following removal of the skin
staples, had abdominal palpation performed twice weekly.
Establishment of the orthotopic phenotype with diffuse peritoneal
spread was accomplished through three serial passes of tumor
tissue. Athymic mice with serially passed tumor tissue grafted onto
their pancreases exhibited a reproducible diffuse peritoneal
metastatic spread from their orthotopically-grafted PDAC
tissue.
Example 4
Administration of the Compound of Formula (I-a-ii) and Gemcitabine
to Mice with Orthotopically Implanted PDAC Tissue and Resulting
Enhancement of Survival
[0198] Seven days following surgical implantation of serially
passed PDAC tumor tissue, mice were randomized into five different
treatment groups. Untreated mice (n=5) received no vehicle or drug
treatments. The vehicle-treated group (n=10) received 100
microliters of the vehicle used for formulation of the compound of
formula (I-a-ii) (40% PEG 1000, 10% povidone, and 2% benzyl
alcohol) s.c. (subcutaneously), BID, five days a week. The first
monotherapy group (n=10) received the compound of formula (I-a-ii)
at 10 mg/kg/dose s.c., BID, five days a week. The second
monotherapy group received gemcitabine at 100 mg/kg/dose i.p.
(intraperitoneally) twice per week in 0.9% saline as described
(Cancer Res. 60: 2926-2935, 2000). The combination therapy group
(n=10) received both the compound of formula (I-a-ii) at 10
mg/kg/dose s.c., BID, five days a week, and gemcitabine at 100
mg/kg/dose i.p. twice per week in 0.9% saline as described (Cancer
Res. 60: 2926-2935, 2000).
[0199] Mice were weighed and palpated twice weekly. Mice remained
in the study unless death or overt morbidity occurred. In the
latter case, mice were sacrificed. The criteria used for evaluation
of overt morbidity were a reduction in body weight of greater than
15%, pronounced hunching and lethargy for several days, the
development of ascites that impaired mobility and feeding, or the
development of severe jaundice. Upon necropsy, a thorough
examination of both the abdominal and thoracic cavities was
performed on each mouse in order to determine the extent of gross
metastatic spread of the orthotopically-implanted PDAC tumor.
Weights of the primary pancreatic tumor with attached spleen, liver
and lungs for each mouse were obtained. Primary pancreatic tumor
with attached spleen, liver, mesenteric lymph nodes, hepatic lymph
nodes and other grossly involved tissues including lungs, kidneys
or uterus, were placed in a 10% formalin fixative for
histopathologic analysis.
[0200] Kaplan-Meier-Wilcoxon analysis of survival data was
performed for the days of dosing to death (DDTD) and is shown in
FIG. 1. Administration of the compound of formula (I-a-ii) alone
resulted in a trend toward improved overall survival relative to
administration of controls, but the trend was not significant. The
mean survival time for mice who received the compound of formula
(I-a-ii), vehicle control, or were untreated, was 63 days, 58 days
and 55 days, respectively. The administration of gemcitabine alone
prolonged survival relative to the administration of controls. The
mean survival time for mice who received gemcitabine, vehicle
control, or were untreated, was 97 days, 58 days and 55 days,
respectively. The administration of a combination of the compound
of formula (I-a-ii) and gemcitabine conferred a highly significant
and unexpected improvement in survival relative to administration
of gemcitabine alone, the compound of formula (I-a-ii) alone, or
controls. The mean survival time of mice who received a combination
of the compound of formula (I-a-ii) and gemcitabine, gemcitabine
alone, the compound of formula (I-a-ii) alone, vehicle control, or
were untreated was 126 days, 97 days, 63 days 58 days, and 55 days,
respectively.
Example 5
Statistical Analysis
[0201] The effects of the compound of formula (I-a-ii) and
gemcitabine alone and in combination on survival of tumor-bearing
mice were analyzed by the Kaplan-Meier-Wilcoxon method as required
for data sets using SAS(SAS 6.12, SAS Institute, Inc. Cary, N.C.).
One way ANOVA and Students-Newman-Keuls analyses were used to
compare mean survival times between treatment groups. The effects
of the compound of formula (I-a-ii) and/or gemcitabine on the
weight of primary tumors and incidence of metastatic lesions were
assessed by the Dunnet's Multiple comparison test with p<0.05
deemed significant.
[0202] Combination therapy using the compositions and methods of
the invention has been shown to significantly enhance the survival
of nude mice with orthotopically implanted human pancreatic ductal
adenocarcinoma. The use of the orthotopic model described above
demonstrated a reproducible metastatic phenotype analogous to the
human clinical course, with widely disseminated peritoneal, hepatic
and messenteric lymph node metastases of human pancreatic carcinoma
origin.
[0203] As discussed in detail in the foregoing examples, mice with
orthotopic human PDAC tumor tissue were untreated or were treated
with gemcitabine alone, a trk tyrosine kinase inhibitor (the
compound of formula (I-a-ii)) alone, or a combination of
gemcitabine and the trk tyrosine kinase inhibitor. The mice who
received the combination therapy experienced a significant and
unexpected enhancement in survival relative to the mice who
received either monotherapy. Moreover, the combination treatment
was well-tolerated, with minimal to no toxicity or weight loss
observed over a prolonged period of administration. The combination
therapy methods and compositions of the present invention have thus
been demonstrated to be effective for cancer treatment.
Significantly, the efficacy of the combination therapy for
enhancing survival exceeds the additive effect of the
monotherapies.
Example 6
Administration of the Compound of Formula (III-a-i) and Gemcitabine
to Mice With Orthotopically Implanted PDAC Tissue and Resulting
Enhancement of Survival
[0204] The formulation and administration of the compound of
formula (II-a-i) and gemcitabine alone and in combination on
survival of tumor-bearing mice was carried out using the methods
described in Examples 1, 4, and 5. The data is presented in FIG.
2.
[0205] The disclosures of each patent, patent application and
publication cited or described in this document are hereby
incorporated herein by reference, in their entirety.
[0206] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims.
* * * * *